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. Epub 2018 Aug 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Casein Kinase Ialpha / antagonists & inhibitors*
  • Casein Kinase Ialpha / physiology
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 9 / physiology
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / physiology
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Enhancer Elements, Genetic / genetics
  • Hematopoiesis
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Mice
  • Mice, Inbred C57BL
  • Oncogene Proteins, Fusion / metabolism
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53 / physiology
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Casein Kinase Ialpha
  • Protein-Serine-Threonine Kinases
  • Cdk9 protein, mouse
  • Cyclin-Dependent Kinase 9
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase 7, mouse