Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2

Author(s):Show less -

Serafim, Ricardo A. M. ^{[1, 2]} ; de Souza Gama, Fernando H. ^[3] ; Dutra, Luiz A. ^{[1, 2]} ; dos Reis, Caio V. ^{[1, 2]} ; Vasconcelos, Stanley N. S. ^{[1, 2]} ; Santiago, Andre da Silva ^{[1, 2]} ; Takarada, Jessica E. ^{[1, 2]} ; Di Pillo, Fulvia ^[4] ; Azevedo, Hatylas ^[3] ; Mascarello, Alessandra ^[3] ; Elkins, Jonathan M. ^{[5, 2]} ; Massirer, Katlin B. ^{[1, 2]} ; Gileadi, Opher ^[5] ; Guimaraes, Cristiano R. W. ^[3] ; Counago, Rafael M. ^{[1, 2]}

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, CBMEG, Ctr Quim Med CQMED, BR-13083875 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Inst Biol, Dept Genet & Evolucao, Struct Genom Consortium, BR-13083886 Campinas, SP - Brazil

^[3] Ache Lab Farmaceut SA, Guarulhos, SP - Brazil

^[4] Univ Estadual Campinas, PhD Program Genet & Mol Biol PGBM, BR-13083886 Campinas, SP - Brazil

^[5] Univ Oxford, Nuffield Dept Med, Struct Genom Consortium, Oxford OX3 7DQ - England

• Document type: Journal article
• Source: ACS Medicinal Chemistry Letters; v. 10, n. 9, p. 1266-1271, SEP 2019.
• Web of Science Citations: 0

Abstract

Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs. (AU)

• FAPESP's process: 18/03359-3 - Protein kinase chemical biology center: supporting drug development through open-access research
• Grantee: Fulvia Di Pillo
• Support type: Scholarships in Brazil - Technical Training Program - Technical Training
• FAPESP's process: 18/09475-5 - New approaches to inhibitors for protein kinases MRCKa, MRCKb and MRCKg
• Grantee: Stanley Nunes Siqueira Vasconcelos
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/50724-5 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research
• Grantee: Paulo Arruda
• Support type: Research Grants - Research Partnership for Technological Innovation - PITE
• 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 type: Scholarships in Brazil - Post-Doctorate