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Cell. 2018 Sep 20;175(1):171-185.e25. doi: 10.1016/j.cell.2018.07.045. Epub 2018 Aug 23.

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

Author information

1
The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
2
The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Hematology, Hadassah Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
3
Bioinformatics Unit of the I-CORE Computation Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
4
BioTheryX Inc., San Diego, CA, USA.
5
WuXi AppTec, Shanghai, China.
6
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
7
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
8
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9
The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Pathology, Hadassah Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
10
The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel. Electronic address: yinonb@ekmd.huji.ac.il.

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.

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

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

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