6GZH

Crystal Structure of Human CDK9/cyclinT1 with A86

Summary for 6GZH

• Entry DOI: 10.2210/pdb6gzh/pdb
• Descriptor: Cyclin-dependent kinase 9, Cyclin-T1, [4-[[4-[5-(cyclopropylmethyl)-1-methyl-pyrazol-4-yl]-5-fluoranyl-pyrimidin-2-yl]amino]cyclohexyl]azanium, ... (5 entities in total)
• Functional Keywords: cdk9, kinase inhibitor, a86, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 118856.95

Authors

Ben-neriah, Y.,Venkatachalam, A.,Minzel, W.,Fink, A.,Snir-Alkalay, I.,Vacca, J. (deposition date: 2018-07-04, release date: 2018-08-29, Last modification date: 2024-10-23)

Primary citation

Minzel, W.,Venkatachalam, A.,Fink, A.,Hung, E.,Brachya, G.,Burstain, I.,Shaham, M.,Rivlin, A.,Omer, I.,Zinger, A.,Elias, S.,Winter, E.,Erdman, P.E.,Sullivan, R.W.,Fung, L.,Mercurio, F.,Li, D.,Vacca, J.,Kaushansky, N.,Shlush, L.,Oren, M.,Levine, R.,Pikarsky, E.,Snir-Alkalay, I.,Ben-Neriah, Y.
Small Molecules Co-targeting CKI alpha and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models.
Cell, 175:171-185.e25, 2018

PubMed Abstract: CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2;Flt3 AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.

PubMed: 30146162
DOI: 10.1016/j.cell.2018.07.045

Experimental method

X-RAY DIFFRACTION (3.17 Å)