Design and synthesis of inhibitors for understudied protein kinases related to RNA and epigenetics

• Grant number: 16/25320-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2017
• End date: September 01, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Katlin Brauer Massirer
• Grantee: Ricardo Augusto Massarico Serafim
• Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 18/23322-7 - DESIGN AND SYNTHESIS OF COVALENT INHIBITORS FOR THE PROTEIN KINASE TTK, BE.EP.PD

Abstract

Protein kinases comprise a large family of proteins responsible for ATP-dependent phosphorylation. This event represents the main post-translation signaling mechanism, controlling most of the cellular processes. In the human genome, there are more than 500 kinase proteins (kinome), but only about 10% have been extensively studied, showing the need to better development a kinase inhibitors pipeline in the pharmaceutical industry and academia. In this project we aim to rationally design and synthetize new inhibitors for the kinase proteins SLK and PRP4B. The inhibitors shall be highly selective and prove their biological effect in vitro and in cell lines, towards the target protein kinases. We are also going to evaluate the selectivity of the inhibitors against a panel of 40 kinases representing different branches of the large kinase family. Preliminary results suggest that these kinases are involved in RNA process regulation and chromatin remodeling. The prototypes for inhibitors development for SLK and PRP4B will be the maleimide scaffold and a published starting compound, respectively. Those series will be evaluated by the SAR studies and co-crystallization with the target protein and will be incrementally improved. The biological activity evaluation will be performed by biochemical and cellular assays. This project will be developed within the highly productive Consortium SGC- Unicamp (Structural Genomics Consortium), which has the aim to accelerate discovery of new chemical probes with kinase inhibition function. We expect to generate highly selective inhibitors and to publish them in the open science context of the SGC (PITE FAPESP 2013/50724-5).

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SERAFIM, RICARDO A. M.; DE SOUZA GAMA, FERNANDO H.; DUTRA, LUIZ A.; DOS REIS, CAIO V.; VASCONCELOS, STANLEY N. S.; SANTIAGO, ANDRE DA SILVA; TAKARADA, JESSICA E.; DI PILLO, FULVIA; AZEVEDO, HATYLAS; MASCARELLO, ALESSANDRA; et al. Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2. ACS Medicinal Chemistry Letters, v. 10, n. 9, p. 1266-1271, SEP 2019. (18/03359-3, 18/09475-5, 13/50724-5, 16/25320-6)

SERAFIM, RICARDO A. M.; SORRELL, FIONA J.; BERGER, BENEDICT-TILMAN; COLLINS, ROSS J.; VASCONCELOS, STANLEY N. S.; MASSIRER, KATLIN B.; KNAPP, STEFAN; BENNETT, JAMES; FEDOROV, OLEG; PATEL, HITESH; et al. Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold. Journal of Medicinal Chemistry, v. 64, n. 18, p. 13259-13278, SEP 23 2021. (18/09475-5, 16/25320-6)

SEGRETTI, NATANAEL D.; TAKARADA, JESSICA E.; FERREIRA, MARCOS A., JR.; SANTIAGO, ANDRE DA SILVA; TEODORO, BRUNO V. M.; DAMIAO, MARIANA C. F. C. B.; GODOI, PAULO H.; CUNHA, MICAEL R.; FALA, ANGELA M.; RAMOS, PRISCILA Z.; et al.

Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B

. Bioorganic & Medicinal Chemistry Letters, v. 68, p. 6-pg., 2022-07-15. (19/14275-8, 21/04853-4, 13/50724-5, 16/25320-6, 14/50897-0)