Abstract 4537: VB15010 is a potent PARP1 selective inhibitor and durable trapper with improved pharmacological activities
Authors: Fang Douglas D. , Liu Yueqin , Liu Yang , Zhang Haolong , Wu Jinping , Wei Jie , Sha Wei , Ding Charles Z. 
Published: March 2024

Abstract
PARP inhibitors have become the backbone of therapy for patients bearing cancers with homologous recombination deficiency (HRD). Currently approved PARP inhibitors, such as olaparib, are pan-PARP inhibitors targeting PARP1, PARP2, and other PARP family members. Emerging evidence suggests that targeting PARP1 is sufficient to exert antitumor effect, whereas targeting PARP2 causes hematological toxicity. Consequently, these pan-PARP inhibitors often lead to dose reduction and treatment discontinuation in clinics. Therefore, developing PARP1 selective inhibitors becomes advantageous to improving patient outcomes and broadening the applications of the targeted therapy. To this end, multiple PARP1 selective inhibitors are currently in preclinical or early clinical development worldwide. We report herein preclinical investigation of a novel, potent PARP1 selective inhibitor and durable DNA trapper, VB15010, which demonstrates improved pharmacokinetic (PK) and pharmacodynamics (PD) properties, and antitumor activity in comparison with an advanced agent in clinical development. Comparatively, VB15010 exhibited higher selectivity for PARP1 over other PARP family members (30 to 8,000-fold) in enzymatic assays, and superior selectivity for PARP1- over PARP2-DNA trapping (&gt;1700-fold) in DNA trapping assays. Genetic knockout of PARP1, but not PARP2, abolished inhibition of PARylation by VB15010 in PARP1/2 wild type cells, further validating its PARP1 selectivity. Besides, VB15010 induced substantially more durable PARP1-DNA trapping when compared to the reference agent. In addition, VB15010 demonstrated potent antiproliferative activity in BRCAm or HRD-positive cancer cell lines (IC50 &lt; 100 nM), as well as induced an increase in DNA damage, cell cycle arrest in G2 phase, and apoptosis in BRCA2-deficient cells in vitro. In vivo, VB15010 showed excellent bioavailability in preclinical animal models. Moreover, VB15010 exerted substantial antitumor activity at a dose range from 0.1 to 30 mg/kg, leading to tumor regression at as low as 0.3 mg/kg in BRCAm human cancer cell line-derived and HRD-positive patient-derived mouse xenograft models with an excellent PK-PD correlation. Tumor-to-plasma ratios of drug exposures indicate that VB15010 displayed a preferable tumor tissue distribution compared with the reference agent. Collectively, with improved PK-PD properties, including durable DNA trapping capability, higher apoptosis-inducing potency, and favorable tumor-to-plasma distribution ratio, as well as potent antitumor activity, VB15010 may achieve enhanced clinical efficacy and reduced hematological toxicity with a higher therapeutic index in patients. Its IND filing is expected in the first quarter of 2024.
Citation Format: Douglas D. Fang, Yueqin Liu, Yang Liu, Haolong Zhang, Jinping Wu, Jie Wei, Wei Sha, Charles Z. Ding. VB15010 is a potent PARP1 selective inhibitor and durable trapper with improved pharmacological activities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4537.