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

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

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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