Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy

Abstract

The effective potency and resistance of poly­(ADP-ribose) polymerase (PARP) inhibitors limit their application. Here, we exploit a new paradigm that mimics the effects of breast cancer susceptibility genes (BRCA) mutations to trigger the possibility of synthetic lethality, based on the previous discovery of a potential synthetic lethality effect between bromodomain-containing protein 4 (BRD4) and PARP1. Consequently, the present study describes compound BP44 with high selectivity for BRD4 and PARP1. Fortunately, BP44 inhibits the homologous recombination in triple-negative breast cancer (TNBC) and triggers synthetic lethality, thus leading to cell cycle arrest and DNA damage. In conclusion, we optimized the BRD4-PARP1 inhibitor based on previous studies, and we expect it to become a candidate drug for the treatment of TNBC in the future. This strategy aims to expand the use of PARPi in BRCA-competent TNBC, making an innovative approach to address unmet oncology needs.

Discovery and Proof of Concept of Potent Dual Polθ/PARP Inhibitors for Efficient Treatment of Homologous Recombination-Deficient Tumors

“…Overall, these findings support using IDE95 as a template for designing dual inhibitors targeting Polθ helicase and PARP. We wished to achieve this by incorporating the pharmacophore of Olaparib into our design, which have been extensively utilized in the design of PARP-based dual inhibitors. − …”

Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson’s Disease

“…An in vivo pharmacokinetics study was carried out in male Sprague-Dawley (SD) rats according to our previous reports . Compound 25c dissolved in normal saline for intravenous administration was formulated in 5% DMSO and 10% Solutol.…”

“…An in vivo pharmacokinetics study was carried out in male Sprague-Dawley (SD) rats according to our previous reports. 60 Compound 25c dissolved in normal saline for intravenous administration was formulated in 5% DMSO and 10% Solutol. Healthy SD rats or MPTP-treated SD rats were administered a single concentration of compound 25c at 1 mg/kg by caudal vein injection or intraperitoneal injection.…”

Discovery, Synthesis, and Evaluation of Novel Dual Inhibitors of a Vascular Endothelial Growth Factor Receptor and Poly(ADP-Ribose) Polymerase for BRCA Wild-Type Breast Cancer Therapy

“…During our efforts to overcome existing shortcomings of targeted treatments of BC, our research group has initiated a series of research works concerning VEGFR and PARP. , Presently, a series of novel VEGFR and PARP dual targeting molecules were designed, synthesized, and pharmacologically evaluated. The candidate molecule 14b was identified as an effective VEGFR/PARP dual inhibitor through combining pharmacophores of VEGFR inhibitor pazopanib and PARP inhibitor veliparib.…”