KSQ-4279

Supported by its favorable pharmacokinetic properties, compound 43 exhibited significant in vivo anticancer efficacy in an MDA-MB-436 xenograft model, achieving superior tumor growth inhibition both as monotherapy and in combination with Olaparib compared to KSQ-4279. Collectively, compound 43 emerges as a promising preclinical candidate with translational potential for BRCA-mutated breast cancer.

Besides, at the effective reversal concentrations, KSQ-4279 neither altered expression and localization of ABCB1/ABCG2/ABCC1, nor affected USP1's potential downstream AKT or ERK1/2 signaling. This is the first study to investigate the combination of USP1 inhibitor (KSQ-4279) with traditional chemotherapeutic drugs in reversing MDR, which surprisingly hinted ABCB1, ABCG2, and ABCC1 as the new targets of KSQ-4279, and advocated this promising combination therapy in clinical refractory MDR cancers.

P1, N=250, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | Trial completion date: Jun 2026 --> Nov 2025

RO7623066 (KSQ-4279) reported an acceptable safety profile during a phase I dose escalation study, with anemia being the most common side effect, and demonstrated robust pharmacokinetic, pharmacodynamic, and clinical activity. 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.

P1, N=250, Recruiting, Hoffmann-La Roche | Trial completion date: Jun 2027 --> Jun 2026 | Trial primary completion date: Jun 2026 --> Aug 2025

Herein, we utilized ring-opening and cyclization strategies based on KSQ-4279 to design a novel series of USP1 inhibitors featuring a morpholine scaffold...Importantly, it enhanced the sensitivity of olaparib-resistant cells to olaparib and showed a synergetic effect with andrographolide in BRCA-proficient cancer cells...In the MDA-MB-436 xenograft model, 38-P2 displayed significant, dose-dependent antitumor efficacy. Overall, these findings indicate that 38-P2 is a promising lead compound for further drug development.

These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials. Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor-resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors.

Inhibitor binding drives a substantial increase in thermal stability of USP1, which may be mediated through the inhibitors filling a hydrophobic tunnel-like pocket in USP1. Our results contribute to the understanding of the mechanism of action of USP1 inhibitors at the molecular level.

P1, N=250, Recruiting, Hoffmann-La Roche | N=140 --> 250

In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.

P1, N=140, Recruiting, Hoffmann-La Roche | Trial completion date: Feb 2025 --> Jun 2027 | Trial primary completion date: Jun 2024 --> Jun 2026

P1, N=140, Recruiting, KSQ Therapeutics, Inc. | Active, not recruiting --> Recruiting | N=64 --> 140