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- | MRTX1719 / BMS
Journal: Transcriptome-wide gene expression outlier analysis pinpoints therapeutic vulnerabilities in colorectal cancer. (Pubmed Central) - Mar 12, 2024
As a proof of concept, we found that CRC cell lines lacking expression of the MTAP gene are sensitive to treatment with a PRMT5-MTA inhibitor (MRTX1719). Finally, other tumor types may also benefit from this approach.
- MTAP deleted cancer targeting synthetic lethal therapeutic / Ryvu Therap
Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_6897;
The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies confirm that MTA cooperative PRMT5 inhibitors exert strong synthetic lethal phenotype in MTAP deleted cancers and offer an exciting therapeutic opportunity for a large patient population.
- TNG908 / Tango Therap, MRTX1719 / BMS
PH020-2: an MTA-cooperative PRMT5 inhibitor with excellent selectivity and brain-penetration capability that targets MTAP-deleted tumors (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_6891;
On this basis, MTA cooperative PRMT5 inhibitors (such as MRTX1719 and TNG908) have been designed to stabilize the binding of PRMT5 to MTA, but not SAM, resulting in further improvement of selectivity window. The data suggest that PH020-2 is an MTA-cooperative PRMT5 inhibitor with excellent brain-penetration that selectively targets MTAP-deleted tumors.
- Combination of MTA-cooperative PRMT5 inhibitor and direct mutant-selective KRAS inhibitors as a novel therapeutic approach for MTAP-deficient pancreatic cancer (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_6888;
Our ongoing studies are evaluating the consequences of co-targeting PRMT5 and KRAS on gene expression changes using RNA-Seq and cancer cell signaling pathways using RPPA analyses. In summary, our data support concurrent inhibition of PRMT5 and KRAS as a promising therapeutic strategy for MTAP-deficient KRAS-mutant pancreatic cancer.
- MTAP loss alters the epigenetic landscape and demonstrates superior therapeutic sensitivity to concomitant PRMT5 and PARP inhibition in cholangiocarcinoma (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_6873;
P1/2
This renders selective targeting of MTAP null tumors with agents (MRTX1719, AMG193, TNG462, TNG908) targeting MTA bound PRMT5 (PRMT5:MTA), while sparing surrounding normal MTAP wild-type (WT) tissue...To address this pressing need, we co-treated CCA cell lines with MRTX1719 and PARP inhibitor olaparib...Similar differences in proportion of splicing events were also observed in MTAP loss CCA patient derived xenografts as compared to WT models. Collectively, these data implicate MTAP to be a crucial player in modulation of the chromatin and splicing events that may drive therapeutic response to PRMT5 inhibition.
- MRTX1719 / BMS
The MTA-cooperative PRMT5 inhibitor, MRTX1719, demonstrates increased anti-tumor activity in combination with KRAS mutant-selective inhibitors in MTAP del,KRAS-mutant cancers (Section 28) - Mar 5, 2024 - Abstract #AACR2024AACR_5471;
Finally, an NF1 mutant, MTAP del malignant peripheral nerve sheath tumor (MPNST) PDX model was treated with MRTX1719, the SOS1 inhibitor MRTX0902, or the combination, and a similar increase in anti-tumor activity was observed in the combination treatment compared to either monotherapy alone. These results suggest that the combination of an MTA-cooperative PRMT5 inhibitor with a KRAS mutant selective or KRAS pathway inhibitor may lead to deeper and more durable responses in MTAP del cancer patients with co-alterations in the KRAS pathway.
- MRTX1719 / BMS
LN18-MRTX1719R cell line, a useful cell model for the discovery of the new PRMT5 inhibitors. (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_2595;
The resistance to MRTX1719 of the LN-18-MRTX1719R cell line was highly stable after 20 cell passages. The LN-18-MRTX1719R cell line can be a useful cell line mode in the development of future PRMT5
- | MRTX1719 / Mirati
Journal: Early Clinical Success of MTA-Cooperative PRMT5 Inhibitors for the Treatment of CDKN2A/MTAP-Deleted Cancers. (Pubmed Central) - Nov 4, 2023
In this issue of Cancer Discovery, Engstrom and colleagues report an MTA-cooperative PRMT5 methyltransferase inhibitor MRTX1719 that selectively kills CDKN2A/MTAP-codeleted cancers and demonstrates early efficacy in clinical trials for solid tumors harboring the CDKN2A/MTAP codeletion. See related article by Engstrom et al., p. 2412 (1).
- | MRTX1719 / Mirati
Preclinical, Clinical Trial,Phase II, Journal, Synthetic lethality: MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer. (Pubmed Central) - Nov 3, 2023
MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and MPNST from the Phase 1/2 study.
- MRTX1719 / Mirati
Identification of mechanism-based combination targets effective with the MTA-cooperative PRMT5 inhibitor MRTX1719 for the treatment of MTAP deleted cancers (Section 18; Poster Board #2) - Mar 14, 2023 - Abstract #AACR2023AACR_5005;
P1/2
Further investigation into potential biomarkers conferring sensitivity or resistance to PRMT5 inhibition was also performed using orthogonal datasets including molecular characterization, differential expression, differential splicing and proteomic analysis. These data suggest MRTX1719, an MTA cooperative PRMT5 inhibitor currently in a Phase I clinical trial (NCT05245500), has the potential to be a synthetically lethal precision medicine for multiple indications harboring MTAP del with high unmet medical need either as a single agent or in combination with clinically feasible rational combination partners.
- MRTX1719 / Mirati
A novel MTA-cooperative PRMT5 inhibitor, MRTX1719, stabilizes the ternary MTA-PRMT5 complex and leads to synthetic lethality in MTAP deleted cancers (Section 18; Poster Board #1) - Mar 14, 2023 - Abstract #AACR2023AACR_5004;
These data demonstrate MRTX1719 preferentially and potently binds PRMT5 in the presence of MTA and selectively inhibits MTAP del cancer cell lines. Moreover, the kinetic properties and selectivity profile suggest MRTX1719 will exhibit a significantly improved therapeutic window for the treatment of MTAP del cancer patients.
- | MRTX1719 / Mirati
Journal: Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits. (Pubmed Central) - Dec 23, 2022
Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.
- | MRTX1719 / Mirati
Journal: Atropisomeric Racemization Kinetics of MRTX1719 Using Chiral Solvating Agent-Assisted F NMR Spectroscopy. (Pubmed Central) - Sep 21, 2022
Here, we describe use of the chiral phosphoric acid solvating agent (+)-TiPSY to resolve the signals of atropisomers in F NMR and to use the data to study the kinetics of racemization and determine the rotational energy barrier of clinical compound MRTX1719. This method is complimentary to traditional chiral high-performance liquid chromatography (HPLC) and enhances the toolkit for chiral analysis techniques.
- | MRTX1719 / Mirati
Journal: Developing an atroposelective dynamic kinetic resolution of MRTX1719 by resolving incompatible chemical operations. (Pubmed Central) - Sep 20, 2022
Application toward synthesis of MRTX1719, a densely functionalized active pharmaceutical ingredient (API), improved yield from 37% to 87%. This protocol provides a complementary means to access rotamers which challenge current asymmetric methodologies, and greatly improves sustainability by decreasing the consumption of solvent and advanced synthetic intermediates.
- | MRTX1719 / Mirati
Journal: Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors. (Pubmed Central) - Sep 10, 2022
MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.
- TNG462 / Tango Therap
TNG462 is a potential best-in-class MTA-cooperative PRMT5 inhibitor for the treatment of peripheral MTAP-deleted solid tumors (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_370;
Oral administration of TNG462 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-deleted cancer cells, and optimized pharmacokinetic properties to extend target coverage, TNG462 has the potential for broader and deeper clinical activity in peripheral MTAP-deleted solid tumors.
- ||| Synthetic lethality: Select projects targeting synthetic lethality TNG908 MRTX1719 SKL27969 AMG 193 AG-270 IDE397 JNJ-64619178 PRT543 PRT811 RP-6306 GSK3326595 GSK3368715 PF-06939999 JBI-778 TNG462 ISM020 AGX323 AT101/ AT201 @JacobPlieth @evaluatepharma https://t.co/74gBPzNLcn https://t.co/5Um0uV9GAB (Twitter) - Aug 17, 2022
- ||| MRTX1719 / Mirati
Trial initiation date, Metastases: Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov) - Apr 5, 2022
P1/2, N=339, Recruiting, Sponsor: Mirati Therapeutics Inc.
With enhanced potency and selectivity for MTAP-deleted cancer cells, and optimized pharmacokinetic properties to extend target coverage, TNG462 has the potential for broader and deeper clinical activity in peripheral MTAP-deleted solid tumors. Initiation date: Feb 2022 --> May 2022
- | MRTX1719 / Mirati
Journal, Synthetic lethality: Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers. (Pubmed Central) - Feb 23, 2022
A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719.
- |||||| MRTX1719 / Mirati
Clinical: First in human #clinicaltrial of @Mirati PRMT5 inhibitor MRTX1719 in MTAP deleted cancers (including #PancreaticCancer) https://t.co/dBbO8Dp5mZ (Twitter) - Feb 18, 2022
- ||||| MRTX1719 / Mirati
New P1/2 trial, Metastases: Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov) - Feb 17, 2022
P1/2, N=339, Recruiting, Sponsor: Mirati Therapeutics Inc.
- MRTX1719 / Mirati
Discovery of MRTX1719: A synthetic lethal inhibitor of the PRMT5/MTA complex for the treatment of MTAP-deleted cancers (Room 6C (San Diego Convention Center)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_403;
In contrast, minimal inhibition of PRMT5-dependent SDMA and tumor growth inhibition was observed in MTAP-wild-type tumor xenografts. MRTX1719 possesses favorable drug-like characteristics, and was selected as a development candidate for the treatment of MTAP-deleted cancers.