STRUCTURE BASED OPTIMIZATION OF BENZIMIDAZOLE 4-CARBOXAMIDE SCAFFOLD LED TO PICOMOLAR POLY(ADP-RIBOSE) POLYMERASE INHIBITORS
Date of Award
MS in Pharmaceutical Science
Tanaji T Talele
Poly(ADP-ribose) polymerase 1 (PARP1) is one of several proteins in the PARP superfamily consisting of 17 proteins with a conserved ART domain. Out of the 17 total proteins, 6 show clear evidence of catalytic activity. These 6 proteins are comprised of PARP1 through PARP4 as well as TNKS1 and TNKS2. PARP1 is thoroughly characterized and has been implicated for its role in various forms of cancer. Due to the role PARP1 plays in the DNA repair pathway, targeting PARP1 for inhibition has led to two distinct anticancer strategies. The first focusing on combinatorial drug therapy with a DNA damaging anticancer agent. DNA-damaging anticancer treatments lead to overactivation of DNA repair pathways, which PARP1 is heavily involved in. This can lead to drug resistance, unless PARP1 is adequately inhibited. The second strategy is the PARP1 inhibitor as a single agent treatment to be utilized in DNA repair deficient patients such as BRCA deficiency. Encouraged by the ability of benzimidazole-4-carboxamide-derived lead compound (1, UKTT-15, PARP1 IC50 = 2.6 nM) to form a cytotoxic PARP1/DNA complex, a study was initiated to further improve its potency as a PARP1 inhibitor while also improving upon the sub-optimal chemical/metabolic stability. The current report features the efforts taken to achieve these goals, wherein we optimized 1 via four molecular modifications by: (1) replacing the methyl ester group with a wide range of stable functional groups, (2) replacing the C6-H with a fluorine on the benzimidazole-4-carboxamide scaffold, (3) replacing the piperazine linker with aminomethylazetidine, and (4) testing salt intermediates without the pyrimidine ring. This led to a series of drug-like compounds (e.g., 2 – 23) with lead compounds exhibiting single digit nanomolar to picomolar potency against PARP1. Predicted binding models of target compounds using PARP1-1 co-crystal structure facilitated interpretation of observed structure-activity relationship data. In addition, representative set of compounds showed improved aqueous solubility and stability at pH4.0/7.4 compared to 1. Moreover, a clean selectivity profile of representative set of 6 compounds was observed when screened against kinases (Ser/Thr and tyrosine) at 100 nM.
Coate, Griffin J., "STRUCTURE BASED OPTIMIZATION OF BENZIMIDAZOLE 4-CARBOXAMIDE SCAFFOLD LED TO PICOMOLAR POLY(ADP-RIBOSE) POLYMERASE INHIBITORS" (2021). Theses and Dissertations. 302.
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