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Targeting Transcriptional Dependency in Acute Myeloid Leukemia (AML) with a Covalent Inhibitor of Transcriptional Kinase CDK7

Yixuan Ren, Victoria Brown, Shanhu Hu, Jeremy Lopez, Sofija Miljovska, Darby Schmidt, Michael Bradley, Kevin Sprott, Eric Olson, Christian C. Fritz and Yoon Jong Choi

Abstract

Highly aggressive acute myeloid leukemia (AML) is the most common cause of leukemia-related deaths in the United States. The development of new treatments for acute leukemias that would increase durable responses and improve poor survival rates with manageable toxicity is imperative. Certain cancers, including acute lymphoblastic leukemia (ALL), are dependent on oncogenic transcription factors and are particularly sensitive to selective CDK7 inhibitors (Kwiatkowski et al., 2014; Chipumuro et al., 2014; Christensen 2014).

AML tumors harbor fewer somatic mutations compared to solid tumors and many of these mutations affect proteins critical to gene control, potentially conferring a unique vulnerability to the inhibition of transcriptional processes. CDK7 is a transcriptional kinase that phosphorylates the C-terminal domain of RNA polymerase II, enabling processive transcription. CDK7 has previously been implicated in the regulation of super-enhancer (SE) mediated circuitry.

Here, we report preclinical in vitro and in vivo data in AML with a first-in-class CDK7 inhibitor, SY-351, that covalently targets a cysteine outside the kinase domain, resulting in sustained, highly selective inhibition. SY-351 shows potent inhibition of CDK7 in biochemical (Ki = 62 nM and Kinact = 11.3 hr-1) and cell-based (EC50 = 4.7 nM HL-60) assays and, when profiled against nearly 400 other kinases, exhibits limited off-target inhibition. In in vitro studies, potent and selective inhibition of CDK7 with SY-351 results in rapid induction of apoptosis in AML cell lines, while inducing little to no cell death in normal immortalized cell lines at comparable levels of target engagement.

In vivo, CDK7 inhibition did not show myelosupression that has previously limited the clinical development of pan CDK inhibitors. Orthotopic AML and ALL patient-derived xenotransplants (PDX), treated with SY-351 results in complete responses (CR) where the clearance of blasts from blood and marrow was achieved without body weight changes or cell death in normal hematopoietic cells. These effects led to increased survival in mouse PDX models, and the response was sustained following removal of the drug.

In summary, we describe a first-in-class CDK7 inhibitor that is potent and selective, well tolerated at efficacious doses and that leads to durable, complete responses in PDX models of AML and ALL. These data support the further exploration of this class of compounds for clinical development.

Disclosures Ren: Syros Pharmaceuticals: Employment, Equity Ownership. Brown: Syros Pharmaceuticals: Employment, Equity Ownership. Hu: Syros Pharmaceuticals: Employment, Equity Ownership. Lopez: Syros Pharmaceuticals: Employment, Equity Ownership. Miljovska: Syros Pharmaceuticals: Employment, Equity Ownership. Schmidt: Syros Pharmaceuticals: Employment, Equity Ownership. Bradley: Syros Pharmaceuticals: Employment, Equity Ownership. Sprott: Sprott Biotech LLC: Other: Spouse Kam M. Sprott is a consultant; Syros Pharmaceuticals: Employment, Equity Ownership. Olson: Syros Pharmaceuticals: Employment, Equity Ownership. Fritz: Syros Pharmaceuticals: Employment, Equity Ownership. Choi: Syros Pharmaceuticals: Employment, Equity Ownership.

  • * Asterisk with author names denotes non-ASH members.