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

  • Cell. 2018 Sep 20;175(1):171-185.e25. doi: 10.1016/j.cell.2018.07.045.
Waleed Minzel  1 ,  Avanthika Venkatachalam  1 ,  Avner Fink  1 ,  Eric Hung  1 ,  Guy Brachya  1 ,  Ido Burstain  1 ,  Maya Shaham  1 ,  Amitai Rivlin  1 ,  Itay Omer  1 ,  Adar Zinger  1 ,  Shlomo Elias  2 ,  Eitan Winter  3 ,  Paul E Erdman  4 ,  Robert W Sullivan  4 ,  Leah Fung  4 ,  Frank Mercurio  4 ,  Dansu Li  5 ,  Joseph Vacca  5 ,  Nathali Kaushansky  6 ,  Liran Shlush  6 ,  Moshe Oren  7 ,  Ross Levine  8 ,  Eli Pikarsky  9 ,  Irit Snir-Alkalay  1 ,  Yinon Ben-Neriah  10
Affiliations
  • 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: [email protected].
PMID: 30146162 DOI: 10.1016/j.cell.2018.07.045
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.
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