Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold

Author(s):Show less -

Serafim, Ricardo A. M. ^{[1, 2]} ; Sorrell, Fiona J. ^[3] ; Berger, Benedict-Tilman ^{[4, 5]} ; Collins, Ross J. ^[6] ; Vasconcelos, Stanley N. S. ^{[1, 2]} ; Massirer, Katlin B. ^{[1, 2]} ; Knapp, Stefan ^{[4, 5]} ; Bennett, James ^[3] ; Fedorov, Oleg ^[3] ; Patel, Hitesh ^[6] ; Zuercher, William J. ^[7] ; Elkins, Jonathan M. ^{[1, 3]}

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[2] Univ Campinas UNICAMP, Ctr Med Chem CQMED, Ctr Mol Biol & Genet Engn CBMEG, BR-13083875 Campinas, SP - Brazil

^[3] Univ Oxford, Ctr Med Discovery, Oxford OX3 7DQ - England

^[4] Goethe Univ Frankfurt, Inst Pharmaceut Chem, D-60438 Frankfurt - Germany

^[5] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, Struct Genom Consortium, D-60438 Frankfurt - Germany

^[6] Cardiff Univ, Sch Biosci, Med Discovery Inst, Cardiff CF10 3AT - Wales

^[7] Univ N Carolina, Struct Genom Consortium, UNC Eshelman Sch Pharm, Chapel Hill, NC 27599 - USA

• Document type: Journal article
• Source: Journal of Medicinal Chemistry; v. 64, n. 18, p. 13259-13278, SEP 23 2021.
• Web of Science Citations: 0

Abstract

SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures of exemplar inhibitors bound to SLK and STK10 demonstrated the binding mode of the inhibitors and rationalized their selectivity. Cellular target engagement assays demonstrated the binding of the inhibitors to SLK and STK10 in cells. Further selectivity analyses, including analysis of activity of the reported inhibitors against off-targets in cells, identified compound 31 as the most potent and selective inhibitor of SLK and STK10 yet reported. (AU)

• FAPESP's process: 18/09475-5 - New approaches to inhibitors for protein kinases MRCKa, MRCKb AND MRCKg
• Grantee: Stanley Nunes Siqueira Vasconcelos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/25320-6 - Design and synthesis of inhibitors for understudied protein kinases related to RNA and epigenetics
• Grantee: Ricardo Augusto Massarico Serafim
• Support Opportunities: Scholarships in Brazil - Post-Doctoral