Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models

Waleed Minzel, Avanthika Venkatachalam, Avner Fink, Eric Hung, Guy Brachya, Ido Burstain, Maya Shaham, Amitai Rivlin, Itay Omer, Adar Zinger, Shlomo Elias, Eitan Winter, Paul E. Erdman, Robert W. Sullivan, Leah Fung, Frank Mercurio, Dansu Li, Joseph Vacca, Nathali Kaushansky, Liran ShlushMoshe Oren, Ross Levine, Eli Pikarsky, Irit Snir-Alkalay, Yinon Ben-Neriah*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

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−/−;Flt3ITD AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia. Combined stabilization of p53 and inactivation of oncogene-driving super enhancers offers a therapeutic approach for acute myeloid leukemia.

Original languageAmerican English
Pages (from-to)171-185.e25
JournalCell
Volume175
Issue number1
DOIs
StatePublished - 20 Sep 2018

Bibliographical note

Funding Information:
We thank Amotz Frenkel for assistance with leukemia animal studies, Drs. Kevan Shokat (Cellular and Molecular Pharmacology, UCSF) and Kyle Chen (BioTheryX) for fruitful project discussions, Dr. Mark Minden (Ontario Cancer Institute- Princess Margaret Hospital, Toronto, Canada) for providing AML PDXs, Jeremy Hunt (DiscoverX, Fremont, California, USA) for the compound-kinome interaction analysis and data interpretation, and the Technion Genome Center, Technion-Israel Institute of Technology for sequencing. We are grateful to the Dr. Berta Strulovici, Dr. Noga Kozer and Dr. Haim Barr (The Nancy and Stephen Grand, Israel National Center for Personalized Medicine, The Weizmann Institute, Rehovot, Israel) for running the kinase library screens and Crelux-WuXi AppTec crystallography team (Martinsried, Germany) for assisting in solving the structures of inhibitor-bound CKIα CKIδ and CDK9. We also thank Liming Xue at WuXi AppTec for the synthesis of compounds in Figure 1. This work was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF) (to Y.B.-N., M.O., and E.P.), Israel Science Foundation (ISF)-Centers of Excellence (to Y.B.-N., M.O., and E.P.), the European Research Council within the FP-7 (294390 PICHO to Y.B.-N. and 281738 LIVERMICROENV to E.P.), Israel Cancer Research Fund Professorship (to Y.B.-N.), and Memorial Sloan Kettering Cancer Center Support Grant (NIH P30 CA008748 to R.L.).

Funding Information:
We thank Amotz Frenkel for assistance with leukemia animal studies, Drs. Kevan Shokat (Cellular and Molecular Pharmacology, UCSF) and Kyle Chen (BioTheryX) for fruitful project discussions, Dr. Mark Minden (Ontario Cancer Institute- Princess Margaret Hospital, Toronto, Canada) for providing AML PDXs, Jeremy Hunt (DiscoverX, Fremont, California, USA) for the compound-kinome interaction analysis and data interpretation, and the Technion Genome Center, Technion-Israel Institute of Technology for sequencing. We are grateful to the Dr. Berta Strulovici, Dr. Noga Kozer and Dr. Haim Barr (The Nancy and Stephen Grand, Israel National Center for Personalized Medicine, The Weizmann Institute, Rehovot, Israel) for running the kinase library screens and Crelux-WuXi AppTec crystallography team (Martinsried, Germany) for assisting in solving the structures of inhibitor-bound CKIα, CKIδ and CDK9. We also thank Liming Xue at WuXi AppTec for the synthesis of compounds in Figure 1 . This work was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF) (to Y.B.-N., M.O., and E.P.), Israel Science Foundation (ISF)-Centers of Excellence (to Y.B.-N., M.O., and E.P.), the European Research Council within the FP-7 ( 294390 PICHO to Y.B.-N. and 281738 LIVERMICROENV to E.P.), Israel Cancer Research Fund Professorship (to Y.B.-N.), and Memorial Sloan Kettering Cancer Center Support Grant ( NIH P30 CA008748 to R.L.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • CDK7 inhibitor
  • CDK9/P-TEFb inhibitor
  • CKIα inhibitor
  • MCL1 elimination
  • MDM2 abolishment
  • MYC elimination
  • acute myeloid leukemia
  • blocking transcription elongation
  • p53 activation
  • super-enhancer shutdown

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