4AGW

Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases

Summary for 4AGW

• Entry DOI: 10.2210/pdb4agw/pdb
• Related: 1F1W 1F2F 1NLO 1NLP 1P13 1PRL 1PRM 1RLP 1RLQ 1SRL 1SRM 2PTK
• Descriptor: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE SRC, 3-{2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}-N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromet hyl)phenyl}benzamide, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: atp-binding, lipoprotein, myristate, phosphoprotein, sh2 domain, sh3 domain, transferase
• Biological source: GALLUS GALLUS
• Total number of polymer chains: 2
• Total formula weight: 67153.21

Authors

Weisberg, E.,Choi, H.G.,Seeliger, M.,Gray, N.,Griffin, J.D. (deposition date: 2012-02-01, release date: 2012-02-15, Last modification date: 2024-05-08)

Primary citation

Weisberg, E.,Choi, H.G.,Ray, A.,Barrett, R.,Zhang, J.,Sim, T.,Zhou, W.,Seeliger, M.,Cameron, M.,Azam, M.,Fletcher, J.A.,Debiec-Rychter, M.,Mayeda, M.,Moreno, D.,Kung, A.L.,Janne, P.A.,Khosravi-Far, R.,Melo, J.V.,Manley, P.W.,Adamia, S.,Wu, C.,Gray, N.,Griffin, J.D.
Discovery of a Small-Molecule Type II Inhibitor of Wild-Type and Gatekeeper Mutants of Bcr-Abl, Pdgfralpha, Kit, and Src Kinases: Novel Type II Inhibitor of Gatekeeper Mutants.
Blood, 115:4206-, 2010

PubMed Abstract: Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRalpha (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.

PubMed: 20299508
DOI: 10.1182/BLOOD-2009-11-251751

Experimental method

X-RAY DIFFRACTION (2.6 Å)