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Discovery of 2,6-Dimethylpiperazines as Allosteric Inhibitors of CPS1
Alan Rolfe1, Shihua Yao1, Toung-Vi Nguyen1
1H3 Biomedicine Inc., 300 Technology Square, Fifth Floor, Cambridge, Massachusetts 02139, United States.
Abstract:
Carbamoyl phosphate synthetase 1 (CPS1) is a potential synthetic lethal target in LKB1-deficient nonsmall cell lung cancer, where its overexpression supports the production of pyrimidine synthesis. In other cancer types, CPS1 overexpression and activity may prevent the accumulation of toxic levels of intratumoral ammonia to support tumor growth. Herein we report the discovery of a novel series of potent and selective small-molecule inhibitors of CPS1. Piperazine 2 was initially identified as a promising CPS1 inhibitor through a high-throughput screening effort. Subsequent structure-activity relationship optimization and structure-based drug design led to the discovery of piperazine H3B-616 (25), a potent allosteric inhibitor of CPS1 (IC50 = 66 nM).
Insights
Researchers discovered novel small-molecule inhibitors for Carbamoyl phosphate synthetase 1 (CPS1). These inhibitors show potential for treating LKB1-deficient lung cancer and other cancers by targeting CPS1 activity.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Carbamoyl phosphate synthetase 1 (CPS1) is implicated in LKB1-deficient nonsmall cell lung cancer, supporting pyrimidine synthesis.
- CPS1 overexpression may also aid tumor growth in other cancers by managing intratumoral ammonia levels.
Purpose of the Study:
- To discover and develop novel, potent, and selective small-molecule inhibitors of CPS1.
- To identify potential therapeutic agents targeting CPS1 in cancer treatment.
Main Methods:
- High-throughput screening to identify initial CPS1 inhibitors.
- Structure-activity relationship (SAR) studies and structure-based drug design for optimization.
- Characterization of inhibitor potency using IC50 values.
Main Results:
- Piperazine 2 was identified as an initial promising CPS1 inhibitor.
- Optimization efforts led to the discovery of piperazine H3B-616 (25).
- H3B-616 is a potent allosteric CPS1 inhibitor with an IC50 of 66 nM.
Conclusions:
- Novel small-molecule inhibitors of CPS1 have been successfully developed.
- Piperazine H3B-616 represents a potent allosteric inhibitor with therapeutic potential.
- CPS1 is a viable target for novel cancer therapies, particularly in LKB1-deficient lung cancer.
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