TY - JOUR
T1 - Chemical Probes for Understudied Kinases
T2 - Challenges and Opportunities
AU - Serafim, Ricardo A. M.
AU - Elkins, Jonathan M.
AU - Zuercher, William J.
AU - Laufer, Stefan A.
AU - Gehringer, Matthias
PY - 2022/1/27
Y1 - 2022/1/27
N2 - Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of highquality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed in the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.
AB - Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of highquality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed in the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.
KW - Structure-based design
KW - Targeting chimeras protacs
KW - Dependent protein-kinase
KW - Drug discovery
KW - Irreversible inhibitors
KW - Allosteric activation
KW - Catalytic domain
KW - Aak1 kinase
KW - Live cells
KW - Covalent
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000766751000009&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1021/acs.jmedchem.1c00980
DO - 10.1021/acs.jmedchem.1c00980
M3 - Article
C2 - 34477374
SN - 0022-2623
VL - 65
SP - 1132
EP - 1170
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -
