Structure Based Design of Pol-theta inhibitors

Recombination Therapeutics, Llc, Philadelphia PA

Investigators

Abstract

Acute myeloid leukemia (AML) is the most frequently diagnosed form of acute leukemia in adults, and standard of care treatment involving chemotherapy and/or stem cell transplantation only cures 30-40% of patients. Recent studies show that AMLs with FLT3 receptor activating internal tandem duplication (ITD) mutations (FLT3(ITD)- positive AMLs) become defective in the BRCA1/2 pathway of homologous recombination (HR) following treatment with tyrosine kinase inhibitors (TKi). BRCA-deficiency confers strong sensitivity to DNA damage and/or DNA repair inhibition, and thus presents a promising new therapeutic strategy for AML. We discovered that BRCA-deficient leukemia cells are hyper-dependent on the DNA repair enzyme DNA polymerase theta (Pol?), which is dispensable for normal cells and mice. Pol? is involved in translesion synthesis and the microhomology-mediated end-joining (MMEJ) double-strand break (DSB) repair pathway. Our leading small- molecule Pol? inhibitor (Pol?i) kills AML patient cells co-treated with the TKi quizartinib which causes BRCA-deficiency, whereas quizartinib and Pol?i as single agents shows significantly less killing. These data demonstrate the Pol?i + TKi combination as a promising therapeutic strategy for FLT3(ITD)-positive AML. Pol?i also shows preferential killing of other BRCA-deficient leukemias (ALL, CML) in vitro and in vivo, especially in combination with TKi. In summary, our data discover Pol? as a novel drug target in leukemia, and demonstrate Pol?i + TKi as a promising therapeutic strategy, especially in aggressive FLT3(ITD)-positive AML. In phase I, Recombination Therapeutics, LLC (RTx), a start-up precision oncology company, plans to increase the potency of our leading Pol?i as a novel treatment for FLT3(IDT)-positive AML using X-ray crystallography and structure based optimization/design by developing the following Aims: 1. To solve the co-crystal structure of Pol?-DNA- Pol?i ternary complexes; 2. To optimize Pol?i using structure based optimization/design. In Phase II, RTx aims to achieve the following goals: 1. Further develop our leading Pol?i drug candidate by achieving more favorable ADME and pharmacokinetic parameters; 2. Characterize optimized Pol?i in combination with TKi in FLT3(IDT)-positive AML animal models in vivo.