Structure-Guided Optimization of Replication Protein A (RPA)–DNA Interaction Inhibitors
Replication protein A (RPA) binds single stranded DNA and has vital functions in DNA repair, in DNA replication, and in DNA damage response (DDR). Targeting the RPA–DNA interaction is a promising strategy for developing therapeutic agents for cancers with intrinsic DNA repair and DDR deficiencies.
In this Issue, Turchi and colleagues (DOI: 10.1021/acsmedchemlett.9b00440) report the optimization of one of their previously reported inhibitors of the RPA–DNA interaction, TDRL-551, that exhibited limited solubility and cell permeability. The authors designed analogues of this compound with the goal to enhance potency and physiochemical properties and used molecular docking studies to guide their compound design. SAR exploration and in vitro assessments of RPA inhibition of synthesized analogs led to the identification of new compounds 43, 45, and 46 with enhanced druglike properties. The authors plan to investigate these inhibitors further in future cellular and in vivo studies.
Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1
Carbamoyl phosphate synthetase 1 (CPS1) is involved in ammonia detoxification and catalyzes the formation of carbamoyl phosphate from ammonia, bicarbonate, and two molecules of ATP. CPS1 is overexpressed in several types of cancer and is a promising therapeutic target. A group at H3 Biomedicine recently disclosed the structure of CPS1 inhibitor 1, an allosteric inhibitor that blocks binding of ATP to the carbamate synthetase domain of CPS1. Although a promising proof-of-principle, the previously reported inhibitor had poor potency and suboptimal physicochemical and pharmacokinetic properties.
In this Issue, Rolfe et al. (DOI: 10.1021/acsmedchemlett.0c00145) describe a structure–activity relationship around a second high-throughput screening hit based on a piperazine scaffold. A key takeaway from the structure–activity relationship is the introduction of two methyl groups at the 2- and 6-positions of the piperazine. The activity is optimized when the methyl groups are in the 2R and 6S configurations. A crystal structure rationalizes the preferred stereochemistry and shows an interesting CH−π interaction between the 2-Me and a nearby tryptophan. An optimized compound, H3B-616, inhibits urea production in primary human hepatocytes, but congeners that are inactive against purified enzyme do not show this same cellular activity, providing evidence for target engagement. Overall, H3B-616 has higher potency and improved physicochemical and pharmacokinetic properties, and it is being further examined for use in nonsmall cell lung cancer.
