Abstract LB032: HH102007 is a highly selective and potent PARP1 inhibitor and trapper

Abstract

Abstract PARP1 plays a critical role in DNA repair and represents the pivotal target of first-generation PARP inhibitors to show so-called “synthetic lethal” efficacy in patients with DNA repair deficiency. PARP2 shares high homology with PARP1, but its inhibition has been linked to hematological toxicity caused by PARP inhibitors with no selectivity between PARP1 and PARP2. AstraZeneca developed next-generation PARP inhibitors with better selectivity on PARP1 over PARP2, AZD5305 and AZD9574, both of this new class, are presently in early phase clinical trials.We discovered a highly selective and potent PARP1 inhibitor, HH102007, which was studied extensively using AZ compounds as comparators. In our setting, AZD5305 was more potent than AZD9574 in PARP1-DNA trapping, cell proliferation inhibition and in vivo anti-tumor efficacy, while AZD9574 had a much higher selectivity on PARP1 enzymatic inhibition over PARP2, which led to less hematological toxicity in rat and a wider therapeutic window in preclinical models. HH102007 showed even better selectivity on PARP1 than both compounds in PARPs enzymatic assays. We also showed that HH102007 can form a tighter PARP1-DNA trapping than AZD9574, leading to better potency in DNA damage, immune activation and cancer cell proliferation as AZD5305. HH102007 achieved tumor regression in MDA-MB-436 xenografts at a lower dose than AZD9574, and showed synergistic efficacy in combination with carboplatin in SUM149PT, which was insensitive to AZD9574. As for hematological toxicity, HH102007 up to 25 mg/kg did not reduce reticulocyte in rat while AZD5305 at 1 mg/kg caused reticulocyte reduction in a head-to-head comparison. In summary, HH102007 is a potent PARP1 inhibitor and trapper, with better selectivity and therapeutic window than both AZ compounds. Profile Olaparib AZD5305 AZD9574 HH102007 Potency IC50 & selectivity PARP1 (nM) 0.94 0.46 0.85 0.32 PARP2 (nM) 0.37 9.52 673.73 325.70 Selectivity PARP1/2 0.39 20.59 794.38 1003.70 Cellular potency IC50 (nM) HCC1395 40.03 0.89 13.79 3.62 MDA-MB-436 8.91 1.24 7.37 2.63 DLD-1 (BRCA2 KO) 28.87 1.38 16.51 2.95 SUM149PT NA 43.85 2999.00 69.57 Efficacy in vivo MDA-MB-436 TGI/ORR in 28 days TR>80% at 100 mg/kg* TR>80% at 0.1 mg/kg* PR 0/5 at 0.6mg/kg, TR 55%, PR 4/5 at 2 mg/kg TR 45%, PR 2/5 at 0.6mg/kg, TR 68%, PR 5/5 at 2 mg/kg Hematotoxicity in rat reticulocyte% in 7 days -92.31 at 100 mg/kg -56.55 at 1 mg/kg +10.41 at 100 mg/kg +15 at 25 mg/kg Therapeutic Index Tox/efficacy free drug AUC <0.33 <1.18 >76.5 >655 Citation Format: Yingjie Hou, Shanyun Gao, Shujuan Jiang, Jingjing Li, Chaobo Zhang, Yanxiao Xu, Songda Yu, Lei Liu, Bing Yu, Wangyang Tu, Yixiang Zhang, Leping Li. HH102007 is a highly selective and potent PARP1 inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB032.