Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto

• Processo: 13/50724-5
• Modalidade de apoio: Auxílio à Pesquisa - Parceria para Inovação Tecnológica - PITE
• Data de Início da vigência: 01 de março de 2015
• Data de Término da vigência: 29 de fevereiro de 2020
• Área do conhecimento: Interdisciplinar
• Pesquisador responsável: Paulo Arruda
• Beneficiário: Paulo Arruda
• Instituição Sede: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brasil
• Município: Campinas
• Instituição parceira: Structural Genomics Consortium
• Pesquisadores principais: Aníbal Eugênio Vercesi ; Licio Augusto Velloso ; Mario Jose Abdalla Saad ; Paulo Mazzafera ; Ronaldo Aloise Pilli
• Auxílio(s) vinculado(s): 15/50024-9 - An integrative analysis of protein kinases in childhood acute lymphoblastic leukemia, AP.R SPRINT
• Bolsa(s) vinculada(s): 19/18771-0 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 19/02059-9 - Centro de biologia quimica de proteinas quinases - alavancando desenvolvimento de farmacos atraves de pesquisa de acesso aberto, BP.TT; 19/02158-7 - Centro de biologia quimica de proteinas quinases - alavancando desenvolvimento de farmacos atraves de pesquisa de acesso aberto, BP.TT; + mais bolsas vinculadas 19/00202-9 - Centro de biologia quimica de proteinas quinases - alavancando desenvolvimento de farmacos atraves de pesquisa de acesso aberto, BP.TT; 18/09342-5 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 18/11871-6 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 18/07844-3 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 18/02528-6 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 18/03063-7 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 18/03359-3 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 17/21179-0 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 17/19894-2 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 17/19605-0 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 17/16063-2 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 17/08535-1 - Centro de Biologia Química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 17/05697-0 - Centro de biologia química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 17/02579-7 - Centro de biologia química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 16/23532-6 - Centro de biologia química de proteínas quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 16/09041-0 - Centro de Biologia Química de Proteínas Quinases - alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 16/08930-5 - Centro de Biologia Química de Proteínas Quinases - alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 16/05692-6 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 16/03526-1 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT; 15/12768-6 - Centro de Biologia Química de Proteínas Quinases: alavancando desenvolvimento de fármacos através de pesquisa de acesso aberto, BP.TT - menos bolsas vinculadas
• Assunto(s): Química Proteínas quinases Angiogênese Desenvolvimento de fármacos Fármacos
• Palavra(s)-Chave do Pesquisador: Chemical Biology | Drug Development | Open Access | Under Explored Kinases

Resumo

The > 500 protein kinases in the human genome are key regulators of virtually every physiological process. Kinases can be targeted by highly potent and selective small molecules. However, despite their importance and suitability for drug discovery, most academic and pharmaceutical research has focused on a small fraction of kinases; most kinases are “under-explored”. These under-explored kinases represent a rich source of new biology and are the focus of this proposal. The UNICAMP proposes to partner with the Structural Genomics Consortium (SGC) to focus on a target list of 26 under-explored kinases implicated in the regulation of RNA splicing and chromatin biology, and that linked to neurological diseases, angiogenesis, and cancer. From these kinases, SGC-UNICAMP aims to generate selective small molecule inhibitors (“chemical probes”) for at least 8. To accomplish this, we will establish a “structure-guided medicinal chemistry” platform (SGC-UNICAMP), with funding and advice from the SGC and its eight pharmaceutical partners and an external advisory board comprising leaders in chemical biology. The platform in collaboration with a network of academics in Campinas and around the world, will characterize the probes in biochemical assays to establish potency and selectivity, and in cellular assays to demonstrate “on-target engagement” in cells. Once the chemical probes meet stringent quality criteria, we will make them available to Brazilian and international scientists without restriction on use. The availability of these chemical probes will uncover new biological pathways and identify new opportunities for therapeutic intervention. By establishing the open access chemistry platform at UNICAMP, we hope to establish UNICAMP as one of the world center of kinase chemical biology. (AU)

Publicações científicas

(30)

(Referências obtidas automaticamente do Web of Science e do SciELO, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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, 17/05697-0, 13/50724-5, 16/09041-0)

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)

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)

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)

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)

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)