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Differences in CDK7 and CDK12 Biology Point to Distinct Therapeutic Strategies

Additional Presentations Highlight Power of Syros’ Gene Control Platform to Identify New Drug Targets Across a Range of Cancers

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, today announced new preclinical data showing that inhibiting cyclin-dependent kinase 7 (CDK7) results in different transcriptional effects than inhibiting cyclin-dependent kinase 12 (CDK12), pointing to distinct therapeutic opportunities to benefit patients with difficult-to-treat cancers. Building on its leadership in gene control, Syros also described new methods for identifying essential genes and transcriptional dependencies in cancer that could serve as potential drug targets. These data were presented at the 2020 Keystone Symposia Cancer Epigenetics: New Mechanisms and Therapeutic Opportunities.

“Together, these presentations underscore our leadership in CDK inhibition and, more broadly, in the field of gene control,” said Eric R. Olson, Ph.D., Syros’ Chief Scientific Officer. “Our understanding of how regulatory regions of the genome control the expression of genes is growing by leaps and bounds, bringing into reach a wide range of diseases that have long eluded effective treatment with other genomics-based approaches. Our platform allows us to elucidate those regulatory regions to pinpoint which genes to control, in which cells, for which patients, and how best to control the expression of those genes using oral molecules to maximize the chances of providing a profound benefit for patients.”

CDK7 Inhibition and CDK12 Inhibition as Distinct Therapeutic Approaches
Syros scientists studied the transcriptional effects of selective CDK7 and CDK12 inhibition in an ovarian cancer cell line, marking the first reported direct comparison of these two approaches. CDK7 and CDK12 are members of the CDK family that have emerged as potentially important drug targets in cancer because of their roles in transcription, the process by which genes express proteins. The findings showed that, under the conditions tested, CDK7 and CDK12 inhibition had distinct effects despite decreasing expression of many of the same genes:

  • CDK7 decreased expression of more genes.
  • CDK12 inhibition preferentially decreased expression of genes with longer transcripts, a phenomenon that was not observed with CDK7 inhibition.
  • The DNA double-stranded break repair pathway is enriched for genes with longer transcripts that are preferentially downregulated by CDK12 inhibition.
  • CDK12 inhibition induced DNA damage, while CDK7 inhibition did not.

The results suggest that a selective CDK12 inhibitor presents distinct therapeutic opportunities from a selective CDK7 inhibitor, such as increasing the susceptibility of cancer to targeted therapies involved in DNA damage repair such as PARP1 inhibitors.

Syros has a highly selective and potent oral CDK7 inhibitor, SY-5609, currently in a Phase 1 trial in patients with advanced breast, colorectal, lung or ovarian cancer, or with solid tumors of any histology that harbor Rb pathway alterations. In addition to decreasing the expression of cancer-driving genes, CDK7 inhibition has also been shown to interfere with cancer’s ability to progress unchecked through the cell cycle. Syros also has a CDK12/13 inhibitor program in preclinical development in cancer.

Building on its Leadership in Gene Control
Syros scientists also presented on two new methods for identifying genes and transcriptional regulators upon which cancer cells are particularly dependent for their survival with the aim of identifying new drug targets.

By analyzing cancer cells with gene copy-number deletions, Syros scientists identified approximately 200 genes that represent dose-dependent transcriptional liabilities across several cancers, including general regulators of transcription that may be attractive drug targets in genetically defined tumor types. Since cancers with copy-number deletions may be more dependent on these regulators than non-cancerous cells, inhibiting them may kill cancer cells while sparing non-cancerous cells. Syros presented preclinical data on one of these transcriptional regulators, INTS11, showing that a glioblastoma cancer cell line with a 1p36-deletion, which is commonly associated with INTS11 copy-number loss, is more sensitive to decreased levels of INTS11 than a cell line without a 1p36-deletion.

In a separate presentation, Syros scientists presented data showing that its new computational model, PETCERF, outperforms earlier-generation models used to score individual enhancers to identify genes critical for a cancer cell’s survival. By integrating multiple variables and inputs related to the enhancer and gene regulatory landscapes into a machine learning model trained using CRISPR knock-out data, PETCERF was shown to identify genes in primary tumor samples that are essential to cancer cells.

Additionally, Dr. Olson will present tomorrow during an oral session on how Syros’ gene control platform has led to a pipeline of small-molecule drug candidates that control the expression of genes with the aim of providing much-needed new medicines for patients with a range of blood cancers and solid tumors.

About Syros Pharmaceuticals
Syros is redefining the power of small molecules to control the expression of genes. Based on its unique ability to elucidate regulatory regions of the genome, Syros aims to develop medicines that provide a profound benefit for patients with diseases that have eluded other genomics-based approaches. Syros is advancing a robust pipeline, including SY-1425, a first-in-class oral selective RARα agonist in a Phase 2 trial in a genomically defined subset of acute myeloid leukemia patients, and SY-5609, a highly selective and potent oral CDK7 inhibitor in a Phase 1 trial in patients with select solid tumors. Syros also has multiple preclinical and discovery programs in oncology and monogenic diseases. For more information, visit www.syros.com and follow us on Twitter (@SyrosPharma) and LinkedIn.

Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, including without limitation statements regarding Syros’ ability to identify new drug targets and the benefits of its gene control platform. The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘continue,’’ ‘‘could,’’ ‘‘estimate,’’ ‘‘expect,’’ “hope,” ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’ ‘‘potential,’’ ‘‘predict,’’ ‘‘project,’’ ‘‘target,’’ ‘‘should,’’ ‘‘would,’’ and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various important factors, including Syros’ ability to: advance the development of its programs under the timelines it projects in current and future clinical trials; demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its drug candidates; replicate scientific and non-clinical data in clinical trials; successfully develop a companion diagnostic test to identify patients; obtain and maintain patent protection for its drug candidates and the freedom to operate under third party intellectual property; obtain and maintain necessary regulatory approvals; identify, enter into and maintain collaboration agreements with third parties, including its ability to perform under its collaboration agreements with Incyte Corporation and Global Blood Therapeutics; manage competition; manage expenses; raise the substantial additional capital needed to achieve its business objectives; attract and retain qualified personnel; and successfully execute on its business strategies; risks described under the caption “Risk Factors” in Syros’ Annual Report on Form 10-K for the year ended December 31, 2018 and Quarterly Report on Form 10-Q for the quarter ended September 30, 2019, each of which is on file with the Securities and Exchange Commission; and risks described in other filings that Syros makes with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Syros expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.

Media Contact:
Naomi Aoki
Syros Pharmaceuticals, Inc.
617-283-4298
naoki@syros.com

Investor Contact:
Hannah Deresiewicz
Stern Investor Relations, Inc.
212-362-1200
hannah.deresiewicz@sternir.com

Source: Syros Pharmaceuticals

Released January 29, 2020