In the Quest for Potent and Selective Malic Enzyme 3 Inhibitors for the Treatment of Pancreatic Ductal Adenocarcinoma

Gaurav Sheth; Shailesh R Shah; Prabal Sengupta; Tushar Jarag; Sabbirhusen Chimanwala; Kalapatapu V V M Sairam; Vaibhav Jain; Rashmi Talwar; Avinash Dhanave; Mehul Raviya; Soumya Menon; Shivangi Trivedi; Trinadha Rao Chitturi

doi:10.1021/acsmedchemlett.2c00369

In the Quest for Potent and Selective Malic Enzyme 3 Inhibitors for the Treatment of Pancreatic Ductal Adenocarcinoma

ACS Med Chem Lett. 2022 Dec 13;14(1):41-50. doi: 10.1021/acsmedchemlett.2c00369. eCollection 2023 Jan 12.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Sun Pharma Advanced Research Company Ltd., Vadodara 390020, India.
² Department of Chemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, India.
³ Department of Chemistry, School of Sciences, Indrashil University, Rajpur 382740, India.
⁴ Department of Bioinformatics and Computational Discovery, Sun Pharma Advanced Research Company Ltd., Vadodara 390020, India.
⁵ Department of in Vitro Biology, Sun Pharma Advanced Research Company Ltd., Vadodara 390020, India.

Abstract

The genome of pancreatic ductal adenocarcinoma (PDAC) is associated with frequent deletion of the tumor suppressor gene SMAD family member 4 (SMAD4) with collateral deletion of its chromosomal neighbor malic enzyme 2 (ME2). In SMAD4 ^-/- /ME2 ^-/- PDAC cells, ME3 takes over the function of the ME2 enzyme, and hence therapeutic targeting of ME3 is expected to arrest tumor growth. Hitherto no selective small molecule inhibitor of ME3 has been reported in the context of PDAC. Based on the molecular docking studies and structure-activity relationships with the reported ME1 inhibitor, several analogues of 6-piperazin-1-ylpyridin-3-ol amides have been synthesized and screened for their ME inhibition activity. Among them, compound 16b is identified as the most potent and selective ME3 inhibitor with an IC₅₀ of 0.15 μM on ME3, and with 15- and 9-fold selectivity over ME1 and ME2, respectively. In the cell viability assay, compound 16b exhibited an IC₅₀ of 3.5 μM on ME2-null PDAC cells, viz., BxPC-3.