NLRP3 Inhibitor (Marianthi) (PFR-4231-100)
NLRP3 Inhibitor (Marianthi) is the small-molecule NLRP3 inhibitor program
under program code PFR-4231-100 and program lead Marianthi. The
corpus material covers an executive-summary status table and Pipeline
CAPS Gantt-style plan, AD evidence and molecular-subtype framing, the
broader NLRP3 inhibitor competitor landscape, in-vivo strategy via
Havrda’s tamoxifen-inducible Nlrp3 mouse and Katy’s ATUKA / BzATP rat
models, the Microglial Imaging cohort plan and TSPO PET tracer
comparison, NHP imaging Bmax / 6OHDA rat ARG and homogenate work, the
Pablo Pelegrin / Proteina speck-bound inflammasome assay matrix and
Co-IP vs WB vs Mass spec vs Pull-down comparison, the di-22:6-BMP
phospholipidosis biomarker safety block, the Established NLRP3 Inhibitor
Screening Flow, and the program’s ShareFolder structure.
This page only collects sources whose nav_path references the program
nav root (with any of the variant spellings NLRP3 inhibitor (Marianthi) (P...), NLRP3 inhibitor (Marianthi), or NLRP3 inhibitor (Marianthi) (PFR-4231-100)). Topic-level cross-axis context (NLRP3 / pyroptosis
biology, CAPS clinical, Imaging neuroinflammation TSPO, Complement /
C5aR1, Havrda / Katy without the program nav root) lives at
inflammation.
Program Overview
The Executive summary on
20240722_183153 records a
status table whose visible header columns are LGE (202102), PE (Dec, 2021), CN (202210), PDE 3/21 (Philip von Rosenstiel, Anne heatherington), CS (202409) RSLT, CDE (PRC) Dec2023→ 202402? → 202507, IND (202508 ← 202410), and pH? (202509 / 202411). Internal
artifacts referenced in the header: NLRP3 Timeline toward CS_202209.pptx,
NLRP3 Inhibitor Global Team_2022.pptx, 0928: TMQB September 2022,
1005: AQB1, 1025: RSLT 15 min: hypothesis/target validation/pharmacology,
10 min: chemistry/safety, 10 min: BM strategy, Meeting 24-25October2022, 중점: andy, ann heatherington. The In vitro and In
vivo planning cells reference human iPSC microglia, microglia from PD patients, TR06802042 (5c) (acieved, preserved verbatim), and
TR06851074 (5c); the In vivo cell records 안 넣기로, against Tox 202501-03 / CS 에 넣겠지. The molecular weight of the homologous cold
compound is recorded as MW: 370.39 (Da이겠지.). Trailing-token
uncertainty around IND (202508) and pH? (202411) is preserved.
The Pipeline CAPS Gantt-style project plan grid on the same page tracks
program rows TR06693098, TR06698660, 2nd atuka, Bz-ATP Rat,
series 5c TR06798980, and RAT formulation pk study across Feb / Mar / Apr / May (early) / June (Late) / July / Aug / Sep / Oct / Nov / Dec / 1 / 2 / 3 / 4 / 5 columns. Per-cell month placement is
approximate; row content is captured in reading order rather than
month-by-month. Yellow-highlighted compound IDs include TR06693098,
TR06698660, the Bz-ATP Rat band, and several lower CSF/plasma
result cells.
The AD evidence block on
20240722_183218 records
three Overall framing bullets: No human genetic link to AD, NLRP3 is not differentially expressed in AD brain but several genes near NLRP3 (GSDMD, IL18 and PYCARD) are up-regulated in parahippocampal gyrus of AD and increased with AD-related pathology burden., and NLRP3-pathway is up-regulated in immune-activated patient group. The MSBB / ROSMAP /
scRNAseq / Emory Mount Sinai per-region table catalogues mRNA Altered?,
∝ each other, and ∝ with Baseline severity/progression? cells; the
Molecular subtypes AD table (A, B1, B2, C1, C2) carries the
Jonghun annotation that NLRP3 (Limitation is that there is no biomarker for discriminating the subgroups. Also even though the NLRP3 pathway is up-regulated in C1 group, it is not specifically higher than the other immune pathways such as 'inflammatory response' (slide #12 heatmap),
and an additional Jonghun annotation that Regarding the C3AR1, the Complement pathway is up regulated even before sub-clustering. AD
biomarker cell values include NLRP3, & IL1B were not available. (MSBB,
ROSMAP) — preserved as a recurring data-availability caveat.
The Competitor landscape spans
20240722_183218 (Genali,
Inzomelid / Inflazome / Roche NCT04015076, Dapansutrile / Olatec
(indeterminate), Neumora 2.1M pounds from Parkinson's UK, Novartis
IFM 2427/DFV890; peripheral NCT04868968, Ventyx VTX2735) and
20240722_183222 (Ventus
VENT-02, Roche RO7486967 / RG-6418 / Selnoflast with Kp,uu: 0.06~0.1,
NodThera NT-0796 P1b/2a HV → PD, Halia, MCC950 NACHT domain /
Walker B binding mechanism). The Inzomelid row notes Ph 1b for PD withdrawn 'strategic decision by sponsor' and Ph 2b for CAPS terminated. The NodThera NT-0796 narrative records ↓ CSF NFL in 7 days by approximately 25% over 7 days in the most inflamed subjects by 13% on average and mean reductions of key pro-inflammatory biomarkers in CSF (e.g. IL-1β, IL-6, CCL2, CXCL1 and CXCL8 (=IL-8)) over 28 days compared to baseline.
The In Vivo strategy strand on
20240722_183231 names the
Compounds, In vivo strategy details, and Cell numbers in AAV1/2 + pSyn mice axes within Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > In Vivo strategy > Havrda > HED > IHC. The Microglial
Imaging cohort plan on
20240722_183244 lays out
the longitudinal cohort table (NET PD FS-ZONE (NCT01280123) Pioglitazone 217 early PD; LCC 200 PD + 230 AJ controls
(Approvable only for LRRK2 study?); PARS 301 prodromal (greyed out);
PPMI 423 PD + 196 hv (replication cohort so has a high bar.,
자격충분); SURE-PD 2 75 early PD (baseline, week 12 (CSF) and months 6 and 18); BioFind discover cohort cross-sectional), the NGP /
Clotilde Degroot meeting 20220727 cohort accounting (PD 24/2/1/21/19,
RBD 34/0/2/32/32**, CTRL 13/0/1/12/4), the C-BIG application notes, and
the [18F]DPA714 / [18F]FEPPA tracer comparison plan with 21129: We are actually having both 18F compounds made (DPA-714 and FEPPA), at our collaborators at DFCI.
The NHP Microglial Imaging axis on
20240722_183255 holds the
Summary tracer-experiment table (Bmax / Invicro / 6OHDA rat / [3H]MCC950 / [3H]Candidate 1 ([3H]TR06616126) / [3H]PBR28) with key
findings High (~10X) SB was observed in both the 1 site and 4 site 6 OHDA lesioned rat brains for [3H]TR06616126 and 92% reduction of [3H]PBR28 / 6m AD vs HC, n=10 each for the postmortem AD section. The
Triaging compounds block transcribes the Anne Kanta 6OHDA rodent
sub-chronic LPS systemic injection design (Normal rat, Low dose LPS (0.5 mpk), High dose LPS (2 mpk), Total 12 arms, if N=3 total experimental rat is 36) and the Dosing regimen sub-table for
TR06647850 at 0.3 mg / 3 mg / 1 h / 2 h time points across WT rat / LPS (0.5 mg/kg) rat / LPS (2 mg/kg) rat. Imaging timeline bullets:
202303: synthesis of precursor of 18F]TR06762852 ongoing,
202304: ship [18F]TR06762852 precursor (5-10mg) and standard (25mg) to Tbos, 202305: Paul Rolzin to surgery (4-level 6OHDA),
202306: Paul Rolzin ship 3-4 rats to Tbos, 202306: label at Dana Farber → PET Study (baseline and blocking?). Candidate compounds: 1st: TR06673219 (TCAL series 3), 2nd: TR06647850 (Novartis Pat.).
The Postmortem / Proteina assay matrix on
20240722_183308 is the
Pablo Pelegrin, Roche (2 times, biofluid) sub-table with columns
Active (Speck-bound) NLRP3 / Active (speck-bound) ASC / Active caspase-1 / GSDMD (N-terminal domain, cleaved) and validation rows for
PMA/Nigericin → ↑ (THP-1), inhibition by MCC950 (THP-1), ↑ il-1b (THP-1), ∝ active GSDMD (thp-1 & MM PBMC). The Proteina assay
development block (Bob.Scienist.com 48D6FD) cites the NLRP3-ASC speck complex measurement need in human/rodent biofluid (CSF and plasma) and
records the per-marker per-species sub-table for NLRP3 / ASC / GSDMD
across Human / Mouse / Rat lines, including human Pharmac modulation
↓ by MCC950 (cs50 19.8 nM in THP1) for ASC. The Proteina vs Charles
River comparison sub-table contrasts (Proteina) Co-IP / WB / Mass spec / Pull-down (Cambridge) on Native vs denatured, Method to detect insoluble proteins / Expression & purification, and Method to detect insoluble proteins / Analysis.
The Reactome / Safety / Screening flow / ShareFolder block on
20240722_183321 holds the
di-22:6-BMP phospholipidosis biomarker discussion (background, rationale
in (Thompson, 2012 #2183) / (Liu, 2014 #2151), normal-range CSF /
plasma / serum / urine sub-table with (Akgoc, 2015 #2192) MW
865.5, and the [20221208] DSRE di-22:6-BMP is a promising, exploratory biomarker for phospholipidosis but is not validated at this point paragraph). The same page carries the multi-coloured Established NLRP3 Inhibitor Screening Flow figure (CHEMISTRY → THP-1-hNLRP3
Caspase-1 IC50 < 500 nM → THP-1-hNLRP3 IL-1β IC50 < 500 nM, # 150
cmp/week → Selectivity & cytotox boxes → Mouse PK/PD → in-vivo efficacy,
with parallel ADMET and Safety/Proarrhythmic/Liver-tox/Genotox tracks)
and the ShareFolder index linking the TCAL/Departments/CNS/PROJECTS/ NLRP3 Inflammasome SharePoint folder, NLRP3 CN Candidate folder ATUKA Vol-1, NLRP3 Timeline toward CS_202308.pptx, Timeline NLRP3 CN Candidates.xlsx, and NLRP3 CNCS candidate assay list.xlsx.
Source Scope And Boundary Notes
The 11-source set follows a relaxed “program nav root appears anywhere
in nav_path” rule rather than the strict “first nav_path entry ==
program nav root” rule. The program nav root appears in three variant
spellings across the corpus:
NLRP3 inhibitor (Marianthi) (P...)(Word truncated-display heading)NLRP3 inhibitor (Marianthi)(without parenthetical)NLRP3 inhibitor (Marianthi) (PFR-4231-100)(full)
Boundary cases worth recording:
- 20240722_183153 carries
the program nav root as the last element of its
nav_path(Pipeline of Inflammation > Pipeline CAPS > Animal model > TM > NLRP3 inhibitor (Marianthi) (PFR-4231-100)); the page is the kickoff transition where the Word cursor crossed from upstream Pipeline CAPS context into the NLRP3 inhibitor program executive summary. It is fully included for evidence because the Executive summary status table and Pipeline CAPS Gantt grid both belong to the program even though the section/by-nav assignment puts the page under upstream axes. - 20240722_183156 and
20240722_183222 are
the only two sources where the program nav root is the first
nav_pathentry; they appear in the nlrp3-inhibitor-marianthi-p per-nav-root index. The other 9 sources do not appear there because their firstnav_pathentry isPipeline of InflammationorInflammation. - 20240722_183159 carries
the variant
Inflammation > NLRP3 inhibitor (Marianthi) > AD > Assays of pyroptosis; it is the same logical content as the abuttingNLRP3 inhibitor (Marianthi) (P...)pages but uses the alternateInflammationfirst-nav root.
Adjacent pages whose nav_path does not reference the program nav
root are excluded from this entity even when they are tightly coupled to
the program in content (e.g. the Havrda KOL pages
20240722_183225 and
20240722_183228, and the
Katy in-vivo pages
20240722_183234,
20240722_183238, and
20240722_183241). They
are catalogued at the topic level under the
KOL (Havrda, Katy)
axis instead.
Evidence Package
| evidence area | source-captured detail | source |
|---|---|---|
| Executive summary status table | Visible columns LGE (202102) / PE (Dec, 2021) / CN (202210) ☐ CN / PDE 3/21 / CS (202409) RSLT / CDE (PRC) Dec2023→ 202402? → 202507 / IND (202508 ← 202410) / pH? (202509 / 202411); artifacts NLRP3 Timeline toward CS_202209.pptx, NLRP3 Inhibitor Global Team_2022.pptx, 0928: TMQB September 2022, 1005: AQB1, 1025: RSLT 15/10/10 min agenda, Meeting 24-25October2022. | 20240722_183153 |
| Pipeline CAPS Gantt-style plan | Rows TR06693098 / TR06698660 / 2nd atuka / Bz-ATP Rat / series 5c TR06798980 / RAT formulation pk study across Feb-Dec / 1-5 columns; series 5c TR06798980 carries the AAV2/5-hα-Syn rat dose-arm protocol (Fischer F344, 4-5 mo, 18 rats per group, bilateral SNpc injection, dose arms 1 mg/kg / 3 mg/kg / 10 mg/kg). | 20240722_183153 |
| In vitro / in vivo program planning | In vitro / 다음 둘 필요 i)human iPSC microglia ii)microglia from PD patients; TR06802042 (5c) acieved 202406; TR06851074 (5c); In vivo / 안 넣기로, / Tox 202501-03 / CS 에 넣겠지. Homologous cold compound MW: 370.39 (Da이겠지.). | 20240722_183153 |
| TR847 deprioritization discussion | Decision criteria TR847 seems less and less appealing while TR084 shows clean profile; TR980 shows comparative potency in BzATP to TR847 and has less concern regarding Br-benzene structure and PK profile; If we drop TR847 we go for AAV model with TR980; Critical data is DSRE cardiomyocyte assay data. | 20240722_183156 |
| TSPO / VMAT2 readout grid | TSPO WB / IHC / ARG [3H]PBR-28 / PET and VMAT2 WB / IHC / ARG / PET ([18F]AV-133) columns; ip LPS rat ARG scatter, y = 0.120·X + 28.3, R² = 0.362, **p = 0.004 ARG vs TSPO IHC; (Sossi 2022 PMID 35524682) aSyn PFF rat DAT OD vs DATscan; (Molinet-Dronda 2015 #2364) 6OHDA rat. Plots kept as evidence (mixed crops). | 20240722_183156 |
| AD in-vivo plan | Animal Tau P301L (=rTg4510 일걸) at ReMynd; Tx systemic LPS vs local BzATP; Read Tau and inflammation. | 20240722_183156 |
| NBB project 1513 AD sample inventory | TAB-approved sample reservation under 1513_Selection_01b.xlsx; AD donors 50 CSF / 21 plasma / 17 frozen hippocampus / 42 paraffin hippocampus; dementia 38/22/27/35; control 50/6/6/21. | 20240722_183156 |
| Assays of pyroptosis matrix | Cell-pellet / human CSF / human blood / PBMC sub-tables citing (Luo 2019 #1852) control n=16, 33.9y, 0.92 ± 0.45 ng/ml, (Peng 2019 #1853) control n=26, 38.8, 대략 <1 ng/ml, (Chatterjee 2020 #1263) iMark Microplate Reader BIORAD, (Fan 2020 #657) PBMC; Havrda MSD detection 0.78 ng/mL LLOQ to 16.2+ ng/mL 90th percentile; Cusabio ELISA (CSB E15885h) LLOQ 0.039 ng/mL, Detection Range 0.156-10 ng/mL; SMCxPro buffer LLOQ 44 pg/mL with S/B 829; CSF 0.17 ng/mL, couldn't get MRD because all diluted samples were below LLOD; plasma 4.45 ng/mL, MRD=2; Issues: low recovery (CSF & plasma), no MRD set up (CSF). | 20240722_183156, 20240722_183159, 20240722_183206 |
| AD evidence overall block | No human genetic link to AD; NLRP3 is not differentially expressed in AD brain but several genes near NLRP3 (GSDMD, IL18 and PYCARD) are up-regulated in parahippocampal gyrus of AD and increased with AD-related pathology burden; NLRP3-pathway is up-regulated in immune-activated patient group. | 20240722_183218 |
| MSBB / ROSMAP / scRNAseq AD per-region table | Brain MSBB N~300 RNA-seq (-Only GSDMD is significantly increased in parahippocampal gyrus of AD(1.3X)(MCI 에선 =), NLRP3 ∝ ASC (coffecient 0.35), NLRP3 ∝ IL18 (coffecient 0.5)); Brain ROSMAP bulk DLPFC N=627 ((의외) NLRP3 and HMGB1 positively ∝ MMSE, (기대) GSDMD negatively ∝ MMSE); ROSMAP scRNAseq DLPFC microglial N=48 (Mathys 2019 #2093); ROSMAP-Emory-Mount Sinai (Johnson 2021 #2048). NLRP3, IL1B, IL18 were not available is recurrent. | 20240722_183218 |
| Molecular subtypes AD | A / B1 / B2 / C1 / C2 with predominant tau / Aβ rows; Immune-related pathways row (B2 / C1 ↑↑ / C2); Jonghun: NLRP3 (Limitation is that there is no biomarker for discriminating the subgroups...); Jonghun: Regarding the C3AR1, the Complement pathway is up regulated even before sub-clustering. | 20240722_183218 |
| Competitor pipeline (Inzomelid / Roche / Ventyx / Novartis / Neumora) | (Genali) BM: PLASMA il-18, csf MCP-1 (=CCL2), CSF NFL; Inzomelid / Inflazome / Roche NCT04015076 SAD & MAD HV & CAPS, Ph 1b for PD withdrawn 'strategic decision by sponsor', Ph 2b for CAPS terminated; Dapansutrile / Olatec (indeterminate); Neumora 2.1M pounds from Parkinson's UK; Novartis IFM 2427/DFV890; peripheral NCT04868968 Ph2 FCAS / Knee osteoarthritis / no brain penetrant compound entering the clinic yet; Canakinumab Ph2 MCI NCT04795466 / Feb 2026; Ventyx VTX2735 Ph2 proof of mechanism for CAPS / 7 patients FCAS / 85% mean reduction in Key Symptom Score during Treatment Period 1; VTX3232 IL-1β IC50 / IC90 coverage in plasma and CSF over 24 hours. | 20240722_183218, 20240722_183222 |
| Competitor pipeline (Ventus / Roche Selnoflast / NodThera / Halia / MCC950) | Ventus VENT-02 P1 ongoing HV/sad/mad / 100% inhibition of IL-1β in blood / Phase 1b PD planned 2H 2024 / Phase 2 treatment-refractory epilepsy 2025; Roche RO7486967 / RG-6418 / Selnoflast / Kp,uu: 0.06~0.1 / ISRCTN85338453 Phase 1b adaptive PD 50-85 / Treatment 28 days / TSPO-PET will be used / BP43176 in NL/UK/USA; NodThera NT-0796 P1b/2a HV→PD / IC50 NDT19795 (PBMC) 52 nM / Day-1/7/28 biomarker grid for IL-1β/IL-6/IL-8/CCL2/CXCL1/NFL/sTREM2 / ↓ CSF NFL by ~25% over 7 days in most inflamed subjects, by 13% on average / 28-day mean reductions in IL-1β/IL-6/CCL2/CXCL1/CXCL8 to HE control levels; NT-0249 peripherally restricted MAD HV completed; NT-0527 DC declared 1Q22 fully brain penetrant; obesity P1b/IIa hsCRP endpoint 28-day; PoC study in RRMS to SPMS and ALS delineated; Halia (las row label clipped) Inflazome NLRP3 PET tracer with MJF funding; MCC950 NACHT-domain Walker-B binding mechanism, BRET closed (resting) vs open (activated) state, ATPase blockade. | 20240722_183222 |
| In Vivo strategy / Havrda axis | Compounds, In vivo strategy details, Cell numbers in AAV1/2 + pSyn mice sub-blocks under Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > In Vivo strategy > Havrda > HED > IHC. | 20240722_183231 |
| Microglial Imaging cohort plan | MJFF Application Aug → review Oct → decision Nov; longitudinal cohorts NET PD FS-ZONE (NCT01280123) Pioglitazone 217 early PD / LCC 200 PD + 230 AJ controls / PARS 301 prodromal / PPMI 423 PD + 196 hv / SURE-PD 2 75 early PD / BioFind discover cohort cross-sectional; PPMI olink CSF&plasma n=~100 longi cytokines; NGP / Clotilde Degroot 20220727 cohort PD 24/2/1/21/19, RBD 34/0/2/32/32**, CTRL 13/0/1/12/4; C-BIG application data-protection / publication clauses; CN-Otake-20220914 CSF!! (only in IL18): 13 HC Logntidunal, zero PD; Olona 2022 #2348 metabolomics. Imaging cost $5,000/person, $500,000/100 persons, $300,000/60 HAB persons. | 20240722_183244 |
| TSPO tracer comparison plan | [18F]DPA714 and [18F]FEPPA tracers under In vitro / In vivo preclinical: single (동물?) / In vivo preclinical 2 → 24 → 48 hr / Patient study / In vivo multiple dose columns; 21129: We are actually having both 18F compounds made (DPA-714 and FEPPA), at our collaborators at DFCI; to assess NLRP3/TSPO relationship at Amsterdam UMC. TSPO SNP rs6971 genotyping (Ala147Thr; A: 20-30%, G: 70-80%; C/C, C/T, T/T binding-affinity classification). | 20240722_183244 |
| NHP / 6OHDA imaging Bmax Summary | Tracer-experiment table Bmax / Invicro / 6OHDA rat (40 µg) striatum / [3H]MCC 950 / [3H]Candidate 1 ([3H]TR06616126) / [3H]PBR28; key results High (~10X) SB observed in both 1 site and 4 site 6OHDA lesioned rat brains for [3H]TR06616126; Binding was notably lower around the 6OHDA lesion site for [3H]MCC950 6 nM; [3H]PBR28 SB window <3X in all regions; postmortem AD section 92% reduction of [3H]PBR28 / 6m AD vs HC, n=10 each and [3H]PBR28 total signal in AD frozen 4-5x higher than that observed using [3H]MCC 950. Postmortem PD samples plan: NBB ARG feasibility ~2 months with [3H]MCC950 and TR126; UK biobank PD brain feasibility evaluation in Jun. Paul Rolzin homogenate confirmation Fold change increase in Total & NSB, BUT very little SB and Dose-dependent increase difference between 6OHDA rat striatum vs naive tissue (5-fold increase in NSB). | 20240722_183255 |
| Triaging compounds (Anne Kanta) / 6OHDA rodent LPS dosing | Sub-chronic LPS systemic injection model (4 times with 0.4 mg/kg i.p.); arms Normal rat 0.3 & 3 mpk / Low dose LPS 0.5 mpk 0.3 & 3 mpk / High dose LPS 2 mpk 0.3 & 3 mpk; Total 12 arms, if N=3 total experimental rat is 36. Dosing regimen sub-table for TR06647850 at 0.3 mg / 3 mg / 1 h / 2 h time points, n=3 per arm. Habituation/dosing schedule cartoon (SD rat 7-8 week, Day 1 Habituation, Days 2-5 LPS i.p., Day 5 TR06647850 i.v., Sampling). Readouts i) brain penetration (Kp), ii) Bmax difference (PD vs WT), iii) regional distribution (SN, striatum?) of the probe (850) by LCMS, iv) block 한다고 안한다고. Imaging timeline 202303-202306 for [18F]TR06762852 precursor synthesis, ship to Tbos, Paul Rolzin 4-level 6OHDA surgery, Dana Farber labelling, baseline and blocking PET. Candidate compounds 1st: TR06673219 (TCAL series 3), 2nd: TR06647850 (Novartis Pat.). | 20240722_183255 |
| Postmortem inflammasome assay matrix (Pablo Pelegrin / Roche) | Speck-bound NLRP3 / ASC / Active caspase-1 / GSDMD (NTD cleaved) detection columns; GFP-NLRP3/mCh-ASC Speck detection in THP-1 is still in progress; GFP-Caspase-1 FL/p20 speck-bound IF (=); GFP-GSDMD FL/NTD MMP THP-1, MultiBO X-1 (THP-1), MM PBMC. Validation PMA/Nigericin → ↑ (THP-1), inhibition by MCC950 (THP-1), ↑ il-1b (THP-1), ∝ active GSDMD (thp-1 & MM PBMC). Vaccari (Univ. of Miami) ASC speck Western from CSF samples of HD and AD patients with ASC speck levels are detected at higher levels in AD CSF compared to HD ※ data X publication ([Vontell, #2250) X. | 20240722_183308 |
| Proteina assay development (NLRP3-ASC speck complex) | Bob.Scienist.com: 48D6FD: Assay development: NLRP-INFLMMASOME; sample-prep needs human/rodent biofluid (CSF and plasma); per-marker per-species Detect / Pharmac / 대체성 / PBMC sub-table for Human / Mouse / Rat × NLRP3 / ASC / GSDMD; ↓ by MCC950 (cs50 19.8 nM in THP1) for human ASC; PBMC 73% / 63% were minimal level (without stimulation), so no window expected; mouse Detected in J774A.1 cells (active form → ↑ by LPS (THP1)) with 20230602 Mouse active NLRP3 assay development is currently in progress. | 20240722_183308 |
| Co-IP vs WB vs Mass spec vs Pull-down comparison | Method comparison sub-table (Proteina) Co-IP / WB / Mass spec / Pull-down (Cambridge) × Native vs denatured / Method to detect insoluble proteins (Expression&purification, Analysis); Pull-down Native (Jain 2019); Mass spec (Trinpus 2009) Solvent-free sample preparation and ionization; WB Blue native gel electrophoresis ... 2D first-dimension native then second-dimension SDS-PAGE. Proteina Q&A (ASC spec (fibril) is insoluble, Antibody binds insoluble?, One signal = one monomer?) vs Charles River (largely should depend on whether antibody recognize insoluble AG, Denature-dilute-capture, Will use → Pre-treatment: NLRP3 / protein → ASC / protein on its). | 20240722_183308 |
| Reactome / Safety: di-22:6-BMP phospholipidosis biomarker | Background: BMP is a negatively charged glycerophospholipid enriched in endosomes/lysosomal membranes. Rationale: (Thompson 2012 #2183, Liu 2014 #2151) urine-d-22-6-BMP correlation with TEM-confirmed PLD-13. Normal range: (Akgoc 2015 #2192) MW 865.5; CSF HC 87.0 ± 130.5 / PD 380.5 ± 174.6 nM; Plasma 0.29 ± 0.15 ng/ml; serum 0.46 ± 0.52 ng/ml; urine creatinine-adjusted HC (n=20) 0.86 ± 1.13 vs NPC (n=21) 44.3 ± 60.9 ng/(mg creatinine). [20221208] DSRE position Di-22:6-BMP is a promising, exploratory biomarker for phospholipidosis but is not validated at this point; alternative biomarkers Glucosylsphingosine, Cathepsin D, LAMP1, Di-22-6-BMP. Lipofuscin detection in eyes if we see such findings in eyes/brains, the progression of the compound would be challenging. | 20240722_183321 |
| Established NLRP3 Inhibitor Screening Flow | Multi-coloured flowchart with explicit IC50 / cmpd-per-week thresholds. Visible nodes: CHEMISTRY # TCAL / # TSHO → THP-1-hNLRP3 Caspase-1 IC50 < 500 nM → THP-1-hNLRP3 IL-1β IC50 < 500 nM, # 150 cmp/week → THP-1 cytotox IC50 > 10 µM, Selectivity hTNFα IC50 > 100X, hNLRP3 [3H]MCC950-Binding # 100 cmp/week, IC50 < 100 nM, J774A.1 mNLRP3 IL-1β IC50 < 100 nM, # 60 cmp/week, m/r NLRP3 [3H]MCC950-Binding IC50 < 100 nM, Mouse brain PK (Kp,uu) Mouse IV (CL and Vd), Mouse PK/PD plasma, Mouse PK/PD brain, In vivo efficacy study. Parallel ADMET track: Cyp Inhibition / Promiscuity < 50%@10 µM / Na channel IC50 > 30 µM (No criteria for Tool compounds) / Solubility JP1/JP2 > 20 µM / Mouse Plasma Protein Binding (rat?) / Rodent brain homogenate Binding / Mouse Hepatocytes and Build IVIVC. Safety track: Safety47 IC50 > 10 µM / Proarrhythmic assay (No predicted risks) / Liver tox assay (indpnero) IC50 > 10 µM / Genotox (Bluescreen); Assess chemotype exemplars prior to PE. Vitro Ad-hoc assays: Human THP-1-IL-18 / LDH / NLRC4 selectivity / SPR Human NLRP3. Vitro rodent assays under development: Mouse/Rat microglia IL-1β assay (CRL) / Mouse Brain slice IL-1β assay (QPS). | 20240722_183321 |
| ShareFolder structure | TCAL/Departments/CNS/PROJECTS NLRP3 Inflammasome SharePoint folder; NLRP3 Inflammasome > QS M&S > Slides-Hamid; InterACT-RAD-Pipeline / NLRP3 Inflammasome / NLRP3 CN Candidate folder; NLRP3 CN Candidate Folder ATUKA Vol-1; 2023 artifacts NLRP3 Timeline toward CS_202308.pptx, Timeline NLRP3 CN Candidates.xlsx, NLRP3 CNCS candidate assay list.xlsx. | 20240722_183321 |
Key Source Interpretations
| interpretation | source |
|---|---|
The program’s executive summary spans LGE 2021/02 → PE Dec 2021 → CN 2022/10 → PDE 3/21 → CS 2024/09 RSLT → CDE 2025/07 → IND 2025/08 → pH? 2025/09, with the IND 2025/08 ← 202410 and pH? (202509 / 202411) tokens preserved as uncertain. | 20240722_183153 |
Series 5c is the program’s lead chemistry: series 5c TR06798980 runs the AAV2/5-h α-Syn rat dose-arm protocol (Fischer F344, 4-5 mo, 18 rats per group, bilateral SNpc, dose arms 1/3/10 mg/kg); TR06802042 (5c) and TR06851074 (5c) are advanced 5c candidates; TR06647850 is the imaging probe cassette under 6OHDA-rat LPS dosing. | 20240722_183153, 20240722_183255 |
| TR847 deprioritization in late 2022 reshaped the chemistry plan: focus moved to TR980 (better profile than TR847 but lower exposure) and TR084 (potentially better exposure than TR980); the AAV alpha-Syn model was committed to TR980 if TR847 dropped, gated by DSRE cardiomyocyte assay data. | 20240722_183156 |
The biomarker plan separates cell-pellet/THP-1 detection from CSF/plasma assay development: SMCxPro buffer LLOQ is 44 pg/mL (S/B 829, 250-fold higher value than that in MSD) but the source flags low recovery (CSF & plasma), no MRD set up (CSF) and couldn't get MRD because all diluted samples were below LLOD, leaving CSF NLRP3 quantitation unresolved at the point of capture. | 20240722_183156 |
AD evidence framing is explicit that NLRP3 is not differentially expressed in AD brain and NLRP3, IL1B, IL18 were not available in the MSBB and ROSMAP protein panels; the NLRP3-pathway up-regulation signal is described at the Molecular subtypes AD C1 group level rather than the disease-vs-control level, and the source flags that no biomarker discriminates the C1 subgroup. | 20240722_183218 |
The Roche selnoflast (RO7486967) Kp,uu: 0.06~0.1 and the Inzomelid Ph 1b for PD withdrawn / Ph 2b for CAPS terminated events define the brain-penetrant NLRP3 inhibitor opportunity space the program is targeting; NodThera NT-0796’s Day 1 / Day 7 / Day 28 biomarker reduction grid (IL-1β -56% / -47%, IL-6 -21% / -54%, CCL2 -20% / -25%, NFL median 7 / 10.5) is the comparator data shape. | 20240722_183218, 20240722_183222 |
Microglial Imaging is the program’s clinical translational biomarker axis: [18F]DPA714 and [18F]FEPPA are co-synthesized at DFCI, 6OHDA rat is the preclinical decision animal model, and the TSPO rs6971 Ala147Thr genotype (A 20-30% / G 70-80%; HAB = A/A) gates patient stratification. | 20240722_183244 |
The NHP imaging Summary tracer table records that [3H]TR06616126 showed High (~10X) SB in 6OHDA rat ARG, [3H]MCC950 showed reduced binding around 6OHDA lesion sites, and [3H]PBR28 had a poor SB window (<3X) in lesioned vs sham hemispheres but a 4-5x higher total signal in AD frozen vs [3H]MCC 950; the Triaging compounds plan focuses on TR06673219 (TCAL series 3) and TR06647850 (Novartis Pat.) as next probes. | 20240722_183255 |
The Postmortem assay strand pairs Pablo Pelegrin / Roche speck-bound detection (THP-1 PMA+Nigericin baseline; inhibition by MCC950 (THP-1)) with Proteina’s Co-IP-based NLRP3-ASC speck assay; the Co-IP / WB / Mass spec / Pull-down method comparison preserves the Charles River caveat that largely should depend on whether antibody recognize insoluble AG, Denature-dilute-capture. | 20240722_183308 |
Safety de-risking centres on di-22:6-BMP as an exploratory phospholipidosis biomarker (DSRE [20221208]); the source explicitly states it is not validated and lists Glucosylsphingosine, Cathepsin D, LAMP1, and Di-22-6-BMP as the alternative biomarker shortlist for the rat 14-day exploratory blood study. | 20240722_183321 |
The Established NLRP3 Inhibitor Screening Flow defines explicit IC50 / cmpd-per-week thresholds (THP-1-hNLRP3 IL-1β IC50 < 500 nM, # 150 cmp/week; hNLRP3 [3H]MCC950-Binding IC50 < 100 nM, # 100 cmp/week; J774A.1 mNLRP3 IL-1β IC50 < 100 nM, # 60 cmp/week; Solubility JP1/JP2 > 20 µM; Genotox (Bluescreen) negative) and is the canonical screening cascade to consult before adding new chemotype filters. | 20240722_183321 |
Source Table
| stem | nav path | source note | canonical | uncertain spans | embedded images |
|---|---|---|---|---|---|
20240722_183153 | Pipeline of Inflammation > Pipeline CAPS > Animal model > TM > NLRP3 inhibitor (Marianthi) (PFR-4231-100) | note | md | 5 | 0 |
20240722_183156 | NLRP3 inhibitor (Marianthi) (P…) > AD > Assays of pyroptosis | note | md | 4 | 0 |
20240722_183159 | Inflammation > NLRP3 inhibitor (Marianthi) > AD > Assays of pyroptosis | note | md | 3 | 0 |
20240722_183206 | Pipeline of Inflammation > Pipeline CAPS > NLRP3 inhibitor (Marianthi) (PFR-4231-100) > AD > Assays of pyroptosis | note | md | 4 | 0 |
20240722_183218 | Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > AD > Chemistry > Clinical > Comp Bio > Competitor | note | md | 4 | 0 |
20240722_183222 | NLRP3 inhibitor (Marianthi) (P…) > Pipeline / Competitors | note | md | 5 | 0 |
20240722_183231 | Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > In Vivo strategy > Havrda > HED > IHC | note | md | 4 | 0 |
20240722_183244 | Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > Katy > Longitudinal > Metabolomics > Microglial Imaging | note | md | 4 | 0 |
20240722_183255 | Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > Microglial Imaging > NHP > PDE > PE > PET | note | md | 5 | 0 |
20240722_183308 | Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > PK/PD > PK/PD Strategy > Postmortem > Proteina | note | md | 4 | 0 |
20240722_183321 | Pipeline of Inflammation > NLRP3 inhibitor (Marianthi) > Reactome > Safety > Screening flow > ShareFolder | note | md | 4 | 0 |
11 sources; uncertain_span_count totals 46; embedded_image_count
totals 0. The zero-figure-embed count reflects the 2026-04-29 body-
purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md):
the Pipeline CAPS Gantt grid, AAV2/5 dose-arm protocol, NodThera Day-
1/7/28 biomarker grid, NHP imaging Bmax tracer matrix, LPS-rat dosing
schedule cartoon, Established NLRP3 Inhibitor Screening Flow chart, and
embedded competitor-slide thumbnails are all kept as evidence rather
than embedded because their crops contain neighbouring cell text.
Figure / Asset Groups In Source
| source | figure group |
|---|---|
| 20240722_183153 | Executive summary status table grid; Pipeline CAPS Gantt-style multi-month plan with colour-band cells (yellow on TR06693098, TR06698660, Bz-ATP Rat; cyan on (6/30) 2w rat tox draft result; pink on CSF/Plasma collected). |
| 20240722_183156 | TSPO ARG / IHC scatter plots (y = 0.120·X + 28.3, R² = 0.362, **p = 0.004); VMAT2 ARG / [11C]-DTBZ PET SB vs DAT(%) scatter (y = 0.792x + 12.557, r = 0.95, p < 0.001); panel C DAT Intensity vs BPND scatter (p < 0.0001, R² = 0.8251, Sossi 2022 PMID 35524682). |
| 20240722_183218 | Competitor pipeline table layout with embedded ClinicalTrials.gov and ISRCTN linkouts. |
| 20240722_183222 | Embedded slide thumbnails (Ventus NLRP3 | Biomarkers of neuroinflammation upregulated in PD patients four-panel scatter; Roche pipeline widget); NodThera multi-column biomarker reduction grid (Healthy elderly control levels set to 100% × IL-1b / IL-6 / IL-8 / CCL2 / CXCL1 / NFL / sTREM2 across Day 1 / Day 7 / Day 28). |
| 20240722_183255 | NHP imaging Bmax / 6OHDA-rat tracer-experiment Summary table; LPS-rat habituation/dosing schedule cartoon (SD rat 7-8 week, Day 1 Habituation, Days 2-5 LPS i.p., Day 5 TR06647850 i.v., Sampling). |
| 20240722_183321 | Established NLRP3 Inhibitor Screening Flow multi-coloured flowchart with parallel ADMET / Safety / Genotox tracks. |
Uncertainties Carried From Source
| issue | source |
|---|---|
Executive summary header column placements (LGE / PE / CN / PDE / CS / CDE / IND / pH?) are reconstructed from the partial text visible across the row strip; column placement and field-vs-content boundaries are partly clipped. | 20240722_183153 |
The TR06802042 (5c) acieved cell preserves the typo acieved (likely achieved); preserved verbatim. | 20240722_183153 |
Pipeline CAPS Gantt grid month resolution: column header strip uses Feb / Mar / Apr / May (early) / June (Late) / July / Aug / Sep / Oct / Nov / Dec / 1 / 2 / 3 / 4 / 5; per-cell column placement is collapsed to reading order rather than month-by-month placement. | 20240722_183153 |
TR06693098 sub-row label reads Sep PQR 9/21 (1.098 & 6602.5c, 3. BM) with the trailing token cluster partly clipped (possibly an internal compound code list). | 20240722_183153 |
TR06798980 / 5. AAV2/5-α-Syn + 10mg/kg row drops the h prefix that rows 2-4 carry (hα-Syn); preserved verbatim, low confidence on whether the prefix omission is intentional. | 20240722_183153 |
Top header row reads correlation), variability는… as a partial leftover from the prior-page table; reading order is preserved as-seen. | 20240722_183156 |
TSPO WB / IHC / ARG / PET cells contain inline scatter plots and box plots; numeric data points and group-label text inside each plot are below legible threshold. VMAT2 ARG panel C axis tick labels (e.g. 6×10⁶) are partially blurred. | 20240722_183156 |
Series 5c bullet tail (If we drop TR847 we go for AAV model with TR980. Meanwhile model is established based on BzATP and TH and PK data.) may continue beyond the visible cell width. | 20240722_183156 |
Quanterix: and Progress sub-blocks on 20240722_183206 carry uncertain row-tail text that should be re-checked before extracting program progress claims. | 20240722_183206 |
Brain MSBB / mRNA cells preserve typo coffecient (likely coefficient); ROSMAP bulk DLPFC mRNA cell preserves GSDSD (instead of GSDMD); preserved verbatim, low confidence on whether GSDSD is a typo or a different gene. | 20240722_183218 |
Molecular subtypes AD column boundaries for B1 / B2 / C1 / C2 are partly inferred from the visible cell text and may not exactly match the source layout. | 20240722_183218 |
Competitor / Inzomelid header reads Inzomelid / Inflazome / Roche; the precise vendor sequence (Roche acquisition timing of Inflazome) is preserved verbatim with low confidence on whether Roche is a separate row or part of the Inflazome row. | 20240722_183218 |
Ventus embedded slide chart (four-panel scatter) and Roche pipeline-widget colour-tagged stage chips are partly below legible threshold; only titles and bullet captions are reliably readable. NodThera Day 7 / Day 28 grid percentages are at the cell edge and NFL = 10.5 and ED50 of 2 mg/kg, EC50 of 74 nM values are best-effort. Halia row leftmost cell label reads las (likely tail of Halia). | 20240722_183222 |
| MJFF cohort table has 6 rows (NET PD FS-ZONE / LCC / PARS / PPMI / SURE-PD 2 / BioFind) and 7-8 visible columns including HC indicator and 약화 status; per-row column placement is partly inferred. | 20240722_183244 |
NGP cohort accounting RBD / Blood* cell reads 32** and the **RBD: 15 have samples from MNI at the W and 14-month follow up, blood TBOS at Sacre-Coeur (Ron Postuma's site) footnote is partly clipped. | 20240722_183244 |
Genotyping DNA level: A→G, Sequence name Change token is followed by a hyperlink that is not legible in the available crop. | 20240722_183244 |
NHP imaging Summary tracer table column placement (Bmax / Invicro / date / study type / sample / Tracer / Competitor / Stimulation / Results / Next study) is partly inferred from cell width; the 202203 Ad hoc 미팅 results cell (Aconita, Ibotia c't qua & comita) carries Korean tokens partly clipped. The Triaging compounds Now immediate next actions ... 3) confirm if TSD can support the WB experiment (Marianthi?) line preserves the parenthetical query. The Imaging timeline tail 202306 is duplicated; preserved verbatim. | 20240722_183255 |
Pablo Pelegrin sub-table column boundaries (Active (Speck-bound) NLRP3 / Active (speck-bound) ASC / Active caspase-1 / GSDMD) are inferred from visible cell text; right-edge clipped. The Mouse (2w) bzATP mouse (CSF, br...) cell trails off (likely brain). The [Inflammasome: NLRP3 oligomerized] / -NLRP3 S-plex: monomer 아닌가? token preserves S-plex verbatim. The Charles River Pre-treatment: NLRP3 / protein (-) → ASC / protein on its (-) workflow note preserves the (-) markers without resolving whether they denote negation or empty cells. | 20240722_183308 |
Rationale Rat: {Thompson, 2012 #2183, 1 rat, DIL422} token DIL422 is preserved as a study/dose code with low confidence on its expansion. Normal-range CSF / Plasma rows mix (Liu, 2014 #2151) and (Akgoc, 2015 #2192) and units (ng/ml / nM); per-source row alignment uncertain. | 20240722_183321 |
| Established NLRP3 Inhibitor Screening Flow chart topology and arrow direction are reproduced via node-label list rather than reconciled topology; per-node arrow direction and IC50 thresholds are preserved with low confidence on the exact arrow sequence. | 20240722_183321 |
ShareFolder SharePoint URLs are partly clipped at the right edge with query parameters (csf=1&e=...&cid=...&FolderCTID=...&View=...); the visible portions are reproduced as anchor text and may not be reachable as-is. | 20240722_183321 |
Related Pages
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- inflammation - section index for Inflammation / NLRP3 / Pyroptosis / Complement
- nlrp3-inhibitor-marianthi-p - per-nav-root index for
NLRP3 inhibitor (Marianthi) (P...)(2 sources where the program is the first nav root) - pipeline-of-inflammation - per-nav-root index for
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nav_paths - parkn-gt - PARKN GT (PFR-4249-100) program entity (sibling internal program; cross-program comparison)
- pr001 - PR001 (GBA gene-therapy comparator)