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Protein Degradation and Inhibitors · Journal article
Journal of Medicinal Chemistry · August 18, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a chemistry-driven preclinical report of a novel USP1 inhibitor (compound 38a) optimized by scaffold hopping. The lead compound shows in vitro potency, cell cycle arrest, synergy with olaparib in a breast cancer cell line, and in vivo antitumor efficacy in a MDA-MB-436 xenograft model (80.7% tumor inhibition) and a DLBCL PDX model. The study represents early translational work and does not contain clinical evidence or human safety data.
Preclinical drug optimization study with in vitro and in vivo efficacy models. MDA-MB-463 and MDA-MB-436 breast cancer cell lines; DLBCL (diffuse large B-cell lymphoma) patient-derived xenograft model; mouse xenograft models. Intervention: 1H-Pyrrolo[3,2-c]pyridine-based USP1 inhibitor (compound 38a), with or without combination with olaparib. Compared with: Olaparib as combination partner; standard first-line therapies (comparator in DLBCL PDX model not specified).
Compound 38a dose-dependently induced Ub-PCNA accumulation and triggered cell cycle arrest in cellular assays In MDA-MB-436 xenograft model, 38a combined with olaparib achieved 80.7% tumor inhibition rate In DLBCL PDX model with high c-MYC expression, 38a demonstrated efficacy comparable to standard first-line therapies
Preliminary safety evaluation mentioned but no detailed safety data provided; no human clinical data
This work identifies a lead USP1 inhibitor warrant of further development. Clinicians and researchers should recognize this as early-stage preclinical validation; progression to clinical trials and human efficacy/safety data will be required before therapeutic application.
Early-stage preclinical chemistry and pharmacology study demonstrating lead compound design and in vivo efficacy in xenograft models, without clinical trial data or regulatory approval.
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This work identifies a lead USP1 inhibitor warrant of further development. Clinicians and researchers should recognize this as early-stage preclinical validation; progression to clinical trials and human efficacy/safety data will be required before therapeutic application.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract USP1, a deubiquitinating enzyme critical for DNA damage repair, represents a promising therapeutic target for cancers. In this study, we employed scaffold hopping to design and synthesize a series of 1H-pyrrolo[3,2-c]pyridine-based USP1 inhibitors. Among these, the lead compound 38a displayed robust enzymatic and cellular potencies. 38a dose-dependently induced Ub-PCNA accumulation, triggered cell cycle arrest, and potently suppressed cell viability. Additionally, 38a synergized with olaparib in MDA-MB-463 cells. Uniquely, 38a effectively induced c-MYC downregulation. In vivo studies confirmed 38a’s favorable oral bioavailability. In the MDA-MB-436 xenograft model, the combination of 38a with olaparib exerted potent antitumor efficacy, with a tumor inhibition rate of 80.7%, and the antitumor activity of 38a stemmed from USP1 inhibition. Furthermore, in the DLBCL PDX model with high c-MYC expression, 38a demonstrated efficacy comparable to standard first-line therapies. Preliminary safety evaluation confirmed the safety profile of 38a. Taken together, 38a is a highly promising antitumor lead compound with great translational potential.
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