- |||||||||| Review, Journal, BRCA Biomarker, PARP Biomarker: USP1 inhibition: A journey from target discovery to clinical translation. (Pubmed Central) - May 25, 2025
Other USP1 inhibitors, including SIM0501, XL309-101, and HSK39775, are currently in early clinical development. In this review, we provide an overview of the molecular function of USP1 and its importance as a therapeutic target in oncology, before focusing on the current state of preclinical and clinical development of USP1 inhibitors.
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INS018-055, A Novel Traf2- and NCK-interacting Kinase (TNIK) Inhibitor, Improves Lung Function in Patients With Idiopathic Pulmonary Fibrosis: Results From a Randomized, Double-blind, Placebo-controlled Phase 2a Study (Room 203-204 (South Building, Level 2), Moscone Center; Poster Board # 101) - Feb 24, 2025 - Abstract #ATS2025ATS_2704; P2 These results suggested that INS018-055 is well-tolerated in IPF patients and demonstrated a dose-dependent effect in lung function improvement within 12 weeks, supporting further development of INS018-055 in larger Phase 2b trials. Figure 1: Descriptive summary of FVC change from baseline at week 12, box plot, mean (SD)
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Clinical, Preclinical, Journal: A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models. (Pubmed Central) - Jan 17, 2025 P1 Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration...A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.
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Enrollment open: Study of ISM3412 in Participants With Locally Advanced/Metastatic Solid Tumors (clinicaltrials.gov) - Jan 5, 2025 P1, N=80, Recruiting, This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline. Not yet recruiting --> Recruiting
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Journal: Discovery of novel MAT2A inhibitors by an allosteric site-compatible fragment growing approach. (Pubmed Central) - Feb 19, 2024 X-ray co-crystal structure revealed that compound 7 fully occupies the allosteric pocket of MAT2A as a single molecule mimicking MAT2B. By introducing additional backbone interactions and rigidifying the requisite linker extensions, we generated compound 8, which exhibited single digit nanomolar enzymatic and sub-micromolar cellular inhibitory potency for MAT2A.
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Journal: Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Inhibitors of CDK8 for the Treatment of Cancer. (Pubmed Central) - May 3, 2023 Here, we report the successful optimization of an azaindole series of CDK8 inhibitors that were identified and further progressed through a structure-based generative chemistry approach. In several optimization cycles, we improved in vitro microsomal stability, kinase selectivity, and in vivo pharmacokinetic profile cross-species, leading to the discovery of compound 23, which demonstrated robust tumor growth inhibition in multiple in vivo efficacy models after oral administration.
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Discovery and evaluation of ISM6466A, a novel covalent CDK12 inhibitor for the treatment of cancer (Section 17; Poster Board #2) - Mar 14, 2023 - Abstract #AACR2023AACR_7165; Results from a 28-day rat DRF study revealed that the compound did not show evident signs of toxicity at the tested doses, suggesting a reasonable safety window for ISM6466A.In summary, the novel, covalent, small-molecule CDK12 inhibitor, ISM6466A, demonstrated excellent preclinical efficacy along with favorable drug-like properties. Our results underscore the therapeutic potential of ISM6466A for the treatment of cancer.
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ISM3412, a novel and selective MAT2A inhibitor for the treatment of cancer (Section 18; Poster Board #3) - Mar 14, 2023 - Abstract #AACR2023AACR_2561; Further, it was well tolerated with no significant hepatobiliary toxicity. In conclusion, ISM3412 is a novel and highly selective MAT2A inhibitor for MTAP-deficient cancers, and merits clinical evaluation.
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ISM3091, a novel selective USP1 inhibitor as a targeted anticancer therapy (Section 18; Poster Board #2) - Mar 14, 2023 - Abstract #AACR2023AACR_2560; ISM3091also displayed very favorable ADME propertiesand PK profiles, and GLP toxicology studies indicated that it was well tolerated without significant gastrointestinal toxicity or hematological toxicity. These data support the future clinical development of ISM3091 as a potential best-in-class USP1 inhibitor not only for PARPi-resistant/responsive HRD-mutant cancers, both, as a single agent as well as in combination with PARPi, but also for subsets of HR-proficient cancers.
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Enrollment open: A Phase 1, Evaluate the Safety, Tolerability, and Pharmacokinetics of INS018_055 in Healthy Subjects (clinicaltrials.gov) - Mar 13, 2022 P1, N=80, Recruiting, These data support the future clinical development of ISM3091 as a potential best-in-class USP1 inhibitor not only for PARPi-resistant/responsive HRD-mutant cancers, both, as a single agent as well as in combination with PARPi, but also for subsets of HR-proficient cancers. Not yet recruiting --> Recruiting
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