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 Shlush; Moshe Oren; Ross Levine; Eli Pikarsky; Irit Snir-Alkalay; Yinon Ben-Neriah

doi:10.1016/j.cell.2018.07.045

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

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

110 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^−/−;Flt3^ITD 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 language	English
Pages (from-to)	171-185.e25
Journal	Cell
Volume	175
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2018.07.045
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2018.07.045

Cite this

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., ... Ben-Neriah, Y. (2018). Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell, 175(1), 171-185.e25. https://doi.org/10.1016/j.cell.2018.07.045

@article{f0eed95d2e164c7daf91dfa6505b55fb,

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

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.",

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",

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

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = sep,

day = "20",

doi = "10.1016/j.cell.2018.07.045",

language = "אנגלית",

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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, PE, Sullivan, RW, Fung, L, Mercurio, F, Li, D, Vacca, J, Kaushansky, N, Shlush, L, Oren, M, Levine, R, Pikarsky, E, Snir-Alkalay, I & Ben-Neriah, Y 2018, 'Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models', Cell, vol. 175, no. 1, pp. 171-185.e25. https://doi.org/10.1016/j.cell.2018.07.045

TY - JOUR

T1 - Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models

AU - Minzel, Waleed

AU - Venkatachalam, Avanthika

AU - Fink, Avner

AU - Hung, Eric

AU - Brachya, Guy

AU - Burstain, Ido

AU - Shaham, Maya

AU - Rivlin, Amitai

AU - Omer, Itay

AU - Zinger, Adar

AU - Elias, Shlomo

AU - Winter, Eitan

AU - Erdman, Paul E.

AU - Sullivan, Robert W.

AU - Fung, Leah

AU - Mercurio, Frank

AU - Li, Dansu

AU - Vacca, Joseph

AU - Kaushansky, Nathali

AU - Shlush, Liran

AU - Oren, Moshe

AU - Levine, Ross

AU - Pikarsky, Eli

AU - Snir-Alkalay, Irit

AU - Ben-Neriah, Yinon

PY - 2018/9/20

Y1 - 2018/9/20

N2 - 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.

AB - 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.

KW - CDK7 inhibitor

KW - CDK9/P-TEFb inhibitor

KW - CKIα inhibitor

KW - MCL1 elimination

KW - MDM2 abolishment

KW - MYC elimination

KW - acute myeloid leukemia

KW - blocking transcription elongation

KW - p53 activation

KW - super-enhancer shutdown

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SN - 0092-8674

VL - 175

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JF - Cell

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

Abstract

Bibliographical note

Keywords

UN SDGs

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