Protein Kinase Chemical Biology Center: supporting drug development through open-access research

• Grant number: 13/50724-5
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• Duration: March 01, 2015 - February 29, 2020
• Field of knowledge: Interdisciplinary Subjects
• Principal Investigator: Paulo Arruda
• Grantee: Paulo Arruda
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City: Campinas
• Partner institutions: Structural Genomics Consortium
• Pesquisadores principais: Aníbal Eugênio Vercesi ; Licio Augusto Velloso ; Mario Jose Abdalla Saad ; Paulo Mazzafera ; Ronaldo Aloise Pilli
• Associated grant(s): 15/50024-9 - An integrative analysis of protein kinases in childhood acute lymphoblastic leukemia, AP.R SPRINT
• Associated scholarship(s): 19/18771-0 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research, BP.TT; 19/02059-9 - PROTEIN KINASE CHEMICAL BIOLOGY CENTER: SUPPORTING DRUG DEVELOPMENT THROUGH OPEN-ACCESS RESEARCH, BP.TT; 19/02158-7 - PROTEIN KINASE CHEMICAL BIOLOGY CENTER: SUPPORTING DRUG DEVELOPMENT THROUGH OPEN-ACCESS RESEARCH, BP.TT; + associated scholarships 19/00202-9 - PROTEIN KINASE CHEMICAL BIOLOGY CENTER: SUPPORTING DRUG DEVELOPMENT THROUGH OPEN-ACCESS RESEARCH, BP.TT; 18/11871-6 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research, BP.TT; 18/09342-5 - Protein kinase Chemical Biology center supporting drug development through open access research, BP.TT; 18/07844-3 - Protein kinase chemical biology center: supporting drug development through open-access research, BP.TT; 18/02528-6 - Protein kinase chemical biology center: supporting drug development through open-access research, BP.TT; 18/03063-7 - Protein kinase chemical biology center: supporting drug development through open-access research, BP.TT; 18/03359-3 - Protein kinase chemical biology center: supporting drug development through open-access research, BP.TT; 17/21179-0 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research, BP.TT; 17/19605-0 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research, BP.TT; 17/08535-1 - Protein Kinase Chemical Biology Center: supporting drug development through open-access research, BP.TT - associated scholarships

Abstract

Mais de 500 proteínas quinases estão presentes no genoma humano, atuando como chaves regulatórias de praticamente todos os processos fisiológicos do organismo humano. As quinases podem ser moduladas através de pequenas moléculas químicas altamente potentes. No entanto, apesar de sua importância e adequação para a descoberta de fármacos, a maioria das pesquisas acadêmicas e farmacêuticas tem se concentrado em apenas uma pequena fração de quinases. Ou seja, a maioria das quinases são “sub-exploradas”. Estas quinases sub-exploradas representam uma rica fonte de inovação em biologia e são o foco deste projeto de pesquisa. A UNICAMP, se propõe a entrar em parceria com o Structural Genomics Consortium (SGC) e conjuntamente trabalhar em uma lista de alvos contendo 26 quinases sub-exploradas envolvidas na regulação do splicing de RNA e da biologia da cromatina – alvos estes implicados em doenças neurológicas, angiogênese e câncer. A SGC-UNICAMP tem como objetivo a geração de pequenas moléculas inibidoras seletivas (“sondas químicas”), para pelo menos oito (8) quinases dessa lista. Para atingirmos esse objetivo, iremos estabelecer uma plataforma de “química medicinal guiada por estruturas” na UNICAMP, com financiamento e aconselhamento dos nossos oito parceiros da indústria farmacêutica e de um conselho consultivo externo composto por líderes globais em biologia química. A plataforma, em colaboração com uma rede de acadêmicos de Campinas e mundial, irá caracterizar as sondas (i) em ensaios bioquímicos, com o objetivo de determinar a potência e a seletividade, e (ii) em ensaios celulares para demonstrar “acoplamento no alvo” no interior das células. Uma vez que as sondas químicas atingirem rigorosos critérios de qualificação, iremos disponibilizá-los para cientistas brasileiros e internacionais, sem restrição de uso. A disponibilidade dessas sondas químicas irá possibilitar a descoberta de novas vias biológicas e identificação de novas oportunidades de intervenção terapêutica. Ao estabelecer esta plataforma química de acesso aberto, temos como objetivo tornar a UNICAMP em um dos centros mundiais em biologia química de quinases. (AU)

Scientific publications

(30)

(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)

JAMIESON, SAM A.; RUAN, ZHENG; BURGESS, ABIGAIL E.; CURRY, JACK R.; MCMILAN, HAMISH D.; BREWSTER, JODI L.; DUNBIER, ANITA K.; AXTMAN, ALISON D.; KANNAN, NATARAJAN; MACE, PETER D.. Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1. Science Signaling, v. 11, n. 549, SEP 25 2018. (13/50724-5)

AQUINO, BRUNO; COUNAGO, RAFAEL M.; VERZA, NATALIA; FERREIRA, LUCAS M.; MASSIRER, KATLIN B.; GILEADI, OPHER; ARRUDA, PAULO. Structural Characterization of Maize SIRK1 Kinase Domain Reveals an Unusual Architecture of the Activation Segment. FRONTIERS IN PLANT SCIENCE, v. 8, MAY 26 2017. (13/50724-5)

KRAHN, ANDREA I.; WELLS, CARROW; DREWRY, DAVID H.; BEITEL, LENORE K.; DURCAN, THOMAS M.; AXTMAN, ALISON D.. Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases. ACS Chemical Neuroscience, v. 11, n. 13, p. 1871-1886, JUL 1 2020. (13/50724-5)

BARRETO, PEDRO; COUNAGO, RAFAEL M.; ARRUDA, PAULO. Mitochondrial uncoupling protein-dependent signaling in plant bioenergetics and stress response. MITOCHONDRION, v. 53, p. 109-120, JUL 2020. (14/50897-0, 16/23218-0, 13/50724-5)

SCOTT, FIONA; FALA, ANGELA M.; PENNICOTT, LEWIS E.; REUILLON, TRISTAN D.; MASSIRER, KATLIN B.; ELKINS, JONATHAN M.; WARD, SIMON E.. Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer. Bioorganic & Medicinal Chemistry Letters, v. 30, n. 8, APR 15 2020. (14/50897-0, 13/50724-5)

RIGHETTO, GERMANNA LIMA; SRIRANGANADANE, DEV; HALABELIAN, LEVON; CHIODI, CARLA G.; ELKINS, JONATHAN M.; MASSIRER, KATLIN B.; GILEADI, OPHER; MENOSSI, MARCELO; COUNAGO, RAFAEL M.. The C-Terminal Domains SnRK2 Box and ABA Box Have a Role in Sugarcane SnRK2s Auto-Activation and Activity. FRONTIERS IN PLANT SCIENCE, v. 10, SEP 17 2019. (13/50724-5)

SANTIAGO, ANDRE DA SILVA; COUNAGO, RAFAEL M.; RAMOS, PRISCILA ZONZINI; GODOI, PAULO H. C.; MASSIRER, KATLIN B.; GILEADI, OPHER; ELKINS, JONATHAN M.. Structural Analysis of Inhibitor Binding to CAMKK1 Identifies Features Necessary for Design of Specific Inhibitors. SCIENTIFIC REPORTS, v. 8, OCT 4 2018. (13/50724-5)

FANTI, REBEKA C.; VASCONCELOS, STANLEY N. S.; CATTA-PRETA, CAROLINA M. C.; SULLIVAN, JARYD R. .; RIBOLDI, GUSTAVO P.; REIS, CAIO V. DOS; RAMOS, PRISCILA Z.; EDWARDS, ALED M.; BEHR, MARCEL A. .; COUNAGO, RAFAEL M.. A Target Engagement Assay to Assess Uptake, Potency, and Retention of Antibiotics in Living Bacteria. ACS INFECTIOUS DISEASES, v. 8, n. 8, p. 19-pg., 2022-07-11. (13/50724-5, 14/50897-0, 18/09475-5)

MEIRELLES, MATHEUS A.; DE TOLEDO, IAN; THUROW, SAMUEL; BARREIRO, GABRIELA; COUNAGO, RAFAEL M.; PILLI, RONALDO A.. Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues. Journal of Organic Chemistry, v. 88, n. 13, p. 13-pg., 2023-06-08. (14/50897-0, 19/25008-0, 19/20735-1, 19/13104-5, 13/50724-5)

JAMIESON, SAM A.; RUAN, ZHENG; BURGESS, ABIGAIL E.; CURRY, JACK R.; MCMILAN, HAMISH D.; BREWSTER, JODI L.; DUNBIER, ANITA K.; AXTMAN, ALISON D.; KANNAN, NATARAJAN; MACE, PETER D.. Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1. SCIENCE SIGNALING, v. 11, n. 549, p. 12-pg., 2018-09-25. (13/50724-5)

FERREIRA, TIAGO R.; COUNAGO, RAFAEL M.; MORETTI, NILMAR S.. Raising the Bar(-seq) in Leishmania Genetic Screens. Trends in Parasitology, v. 37, n. 5, p. 3-pg., 2021-04-14. (18/09948-0, 13/50724-5, 14/50897-0)

WELLS, CARROW; LIANG, YI; PULLIAM, THOMAS L.; LIN, CHENCHU; AWAD, DOMINIK; EDUFUL, BENJAMIN; O'BYRNE, SEAN; HOSSAIN, MOHAMMAD ANWAR; CATTA-PRETA, CAROLINA MOURA COSTA; RAMOS, PRISCILA ZONZINI; et al. SGC-CAMKK2-1: A Chemical Probe for CAMKK2. CELLS, v. 12, n. 2, p. 17-pg., 2023-01-01. (13/50724-5, 14/50897-0)

COUNAGO, RAFAEL M.; ALLERSTON, CHARLES K.; SAVITSKY, PAVEL; AZEVEDO, HATYLAS; GODOI, PAULO H.; WELLS, CARROW I.; MASCARELLO, ALESSANDRA; DE SOUZA GAMA, FERNANDO H.; MASSIRER, KATLIN B.; ZUERCHER, WILLIAM J.; et al. Structural characterization of human Vaccinia-Related Kinases (VRK) bound to small-molecule inhibitors identifies different P-loop conformations. SCIENTIFIC REPORTS, v. 7, AUG 8 2017. (13/50724-5)

AGAJANIAN, MEGAN J.; WALKER, MATTHEW P.; AXTMAN, ALISON D.; RUELA-DE-SOUSA, ROBERTA R.; SERAFIN, D. STEPHEN; RABINOWITZ, ALEX D.; GRAHAM, DAVID M.; RYAN, MEAGAN B.; TAMIR, TIGIST; NAKAMICHI, YUKO; et al. WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop. CELL REPORTS, v. 26, n. 1, p. 79+, JAN 2 2019. (16/17469-0, 13/50724-5)

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)

WELLS, CARROW I.; VASTA, JAMES D.; CORONA, CESEAR R.; WILKINSON, JENNIFER; ZIMPRICH, CHAD A.; INGOLD, MORGAN R.; PICKETT, JULIE E.; DREWRY, DAVID H.; PUGH, KATHRYN M.; SCHWINN, MARIE K.; et al. Quantifying CDK inhibitor selectivity in live cells. NATURE COMMUNICATIONS, v. 11, n. 1, JUN 2 2020. (14/50897-0, 13/50724-5, 16/17469-0)

EDUFUL, BENJAMIN J.; O'BYRNE, SEAN N.; TEMME, LOUISA; ASQUITH, CHRISTOPHER R. M.; LIANG, YI; PICADO, ALFREDO; PILOTTE, JOSEPH R.; HOSSAIN, MOHAMMAD ANWAR; WELLS, I, CARROW; ZUERCHER, WILLIAM J.; et al. Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes. Journal of Medicinal Chemistry, v. 64, n. 15, p. 10849-10877, AUG 12 2021. (19/14275-8, 13/50724-5, 14/50897-0)

HENDERSON, SCOTT H.; SORRELL, FIONA; BENNETT, JAMES; FEDOROV, OLEG; HANLEY, MARCUS T.; GODOI, PAULO H.; DE SOUSA, ROBERTA RUELA; ROBINSON, SEAN; ASHALL-KELLY, ALEXANDER; NAVRATILOVA, IVA HOPKINS; et al. Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors. Journal of Medicinal Chemistry, v. 64, n. 15, p. 11709-11728, AUG 12 2021. (16/17469-0, 13/50724-5)

PROFETA, GERSON S.; DOS REIS, CAIO V.; SANTIAGO, ANDRE DA S.; GODOI, PAULO H. C.; FALA, ANGELA M.; WELLS, CARROW I.; SARTORI, ROGER; SALMAZO, ANITA P. T.; RAMOS, PRISCILA Z.; MASSIRER, KATLIN B.; et al. Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. SCIENTIFIC REPORTS, v. 9, NOV 11 2019. (19/14275-8, 14/50897-0, 13/50724-5)

HERNEISEN, ALICE L.; SIDIK, SAIMA M.; MARKUS, BENEDIKT M.; DREWRY, DAVID H.; ZUERCHER, WILLIAM J.; LOURIDO, SEBASTIAN. Identifying the Target of an Antiparasitic Compound in Toxoplasma Using Thermal Proteome Profiling. ACS Chemical Biology, v. 15, n. 7, p. 1801-1807, JUL 17 2020. (13/50724-5, 16/17469-0)

RIBOLDI, GUSTAVO P.; ZIGWEID, RACHAEL; MYLER, PETER J.; MAYCLIN, STEPHEN J.; COUNAGO, RAFAEL M.; STAKER, BART L.. Identification of P218 as a potent inhibitor of Mycobacterium ulcerans DHFR. RSC MEDICINAL CHEMISTRY, v. 12, n. 1, p. 103-109, JAN 1 2021. (13/50724-5, 14/50897-0)

TOSARINI, THALITA RAVAZO; RAMOS, PRISCILA ZONZINI; PROFETA, GERSON SOUZA; BARONI, RENATA MORO; MASSIRER, KATLIN B.; COUNAGO, RAFAEL M.; MONDEGO, JORGE M. C.. Cloning, expression and purification of kinase domains of cacao PR-1 receptor-like kinases. Protein Expression and Purification, v. 146, p. 78-84, JUN 2018. (13/50724-5, 12/07657-2)

ALVES, FERNANDO RODRIGUES DE SA; COUNAGO, RAFAEL M.; LAUFER, STEFAN. Chemical Space Exploration of Oxetanes. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 21, NOV 2020. (14/50897-0, 13/50724-5)

SILVA, SUELEN FERNANDES; KLIPPEL, ANGELICA HOLLUNDER; RAMOS, PRISCILA ZONZINI; SANTIAGO, ANDREE DA SILVA; VALENTINI, SANDRO ROBERTO; BENGTSON, MARIO HENRIQUE; MASSIRER, KATLIN BRAUER; BILSLAND, ELIZABETH; COUNAGO, RAFAEL MIGUEZ; ZANELLI, CLESLEI FERNANDO. Structural features and development of an assay platform of the parasite target deoxyhypusine synthase of Brugia malayi and Leishmania major. PLoS Neglected Tropical Diseases, v. 14, n. 10, OCT 2020. (13/50724-5, 14/50897-0, 16/16970-7, 15/03553-6, 18/16672-1, 19/14275-8)

ERCOLI, MARIA FLORENCIA; RAMOS, PRISCILA ZONZINI; JAIN, RASHMI; PILOTTE, JOSEPH; DONG, OLIVER XIAOOU; THOMPSON, TY; WELLS, CARROW, I; ELKINS, JONATHAN M.; EDWARDS, ALED M.; COUNAGO, RAFAEL M.; et al. An open source plant kinase chemogenomics set. PLANT DIRECT, v. 6, n. 11, p. 13-pg., 2022-11-01. (13/50724-5, 14/50897-0)

O'BYRNE, SEAN N.; SCOTT, JOHN W.; PILOTTE, JOSEPH R.; SANTIAGO, ANDRE DA S.; LANGENDORF, CHRISTOPHER G.; OAKHILL, JONATHAN S.; EDUFUL, BENJAMIN J.; COUNAGO, RAFAEL M.; WELLS, CARROW I.; ZUERCHER, WILLIAM J.; et al. In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds. Molecules, v. 25, n. 2, JAN 2 2020. (13/50724-5, 19/14275-8, 14/50897-0)

WELLS, CARROW; COUNAGO, RAFAEL M.; LIMAS, JUANITA C.; ALMEIDA, TUANNY L.; COOK, JEANETTE GOWEN; DREWRY, DAVID H.; ELKINS, JONATHAN M.; GILEADI, OPHER; KAPADIA, NIRAV R.; LORENTE-MACIAS, ALVARO; et al. SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K. ACS Medicinal Chemistry Letters, v. 11, n. 3, p. 340-345, MAR 12 2020. (14/50897-0, 13/50724-5, 16/17469-0)

ALAM, MAHMOOD M.; SANCHEZ-AZQUETA, ANA; JANHA, OMAR; FLANNERY, ERIKA L.; MAHINDRA, AMIT; MAPESA, KOPANO; CHAR, ADITYA B.; SRIRANGANADANE, DEV; BRANCUCCI, NICOLAS M. B.; ANTONOVA-KOCH, YEVGENIYA; et al. Validation of the protein kinase PfCLK3 as a multistage cross-species malarial drug target. Science, v. 365, n. 6456, p. 884+, AUG 30 2019. (13/50724-5)

ALVES BARBOSA, EVERTON DE ALMEIDA; SERAPHIM, THIAGO VARGAS; GANDIN, CESAR AUGUSTO; TEIXEIRA, LEILANE FERREIRA; GONCALVES DA SILVA, RONNI ANDERSON; RIGHETTO, GERMANNA L.; GONCALVES, KALIANDRA DE ALMEIDA; VASCONCELLOS, RAPHAEL DE SOUZA; ALMEIDA, MARCIA ROGERIA; SILVA JUNIOR, ABELARDO; et al. Insights into the full-length SRPK2 structure and its hydrodynamic behavior. International Journal of Biological Macromolecules, v. 137, p. 205-214, SEP 15 2019. (14/07206-6, 13/50724-5, 11/23110-0, 12/00195-3, 17/03489-1, 12/50161-8, 17/07335-9)

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)