On January 29, 2020 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported 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 (Press release, Syros Pharmaceuticals, JAN 29, 2020, View Source [SID1234553664]). 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.

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"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.