Development of Best-in-Class Pol-Theta Inhibitors

Project summary. BRCA1 and BRCA2 facilitate DNA double-strand break (DSB) repair via homologous recombination (HR). Yet BRCA1/2 are often mutated in cancers, such as breast/ovarian/prostate/pancreatic carcinomas. BRCA-deficient cancer cells are therefore HR-defective, and susceptible to agents that induce DNA damage and/or prevent DSB repair. For instance, Poly-ADP ribose polymerase 1 (PARP1) inhibitors (PARPi) preferentially kill BRCA-deficient cancer cells and are approved to treat HR-deficient cancers. However, only ~60% patients respond to PARPi and drug resistance is a major problem. Thus, developing second-generation precision medicines that target HR-deficient cancers and/or overcome PARPi resistance is urgently needed. DNA polymerase theta (Polq), a DNA repair factor important for microhomology-mediated end-joining (MMEJ) of DSBs, has been recently validated as a druggable target in BRCA-deficient cancers. Polq is essential for BRCA-deficient cancer cells, but is dispensable for BRCA-proficient cells, and Polq null mice exhibit no major phenotypes. Recently reported Polq inhibitors (Polqi) showed preferential killing of BRCA-deficient cells. Yet, these early stage inhibitors have significant deficiencies (i.e. poor ADME and PK parameters, or low potency) which may limit their efficacy in clinical studies. We have developed a novel, oral bioavailable Polqi that exhibits 5.1 nM IC50 against Polq polymerase (Polq-pol), selectively kills BRCA-deficient cells, and exhibits better pharmacokinetics than recently published Polqi. Our collaborative team (Pomerantz, Johnson, and Childers labs) plans to further improve and demonstrate proof-of-principle of our novel Polqi as the potentially best-in-class Polqi by developing the following Aims: 1. Optimization of Polqi via a prodrug strategy; 2. Biochemical and cellular characterization of Polqi; 3. In vivo efficacy of optimized Polqi in BRCA-deficient solid tumors. We expect that successful completion of these Aims will enable the development of a potentially best-in-class Polqi prodrug candidate.