On April 8, 2022 Syros Pharmaceuticals (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, reported new preclinical data from our CDK12 inhibitor program, demonstrating robust anti-tumor activity of our oral, selective CDK12 inhibitors in models of breast, lung, and ovarian cancer, including in a PARP inhibitor resistant model (Press release, Syros Pharmaceuticals, APR 8, 2022, View Source [SID1234611763]). The data support the advancement of a development candidate from Syros’ CDK12 inhibitor program towards clinical development. These findings were presented in an e-poster as part of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022.
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"CDK12 is an attractive cancer target due to its role in transcription and DNA damage repair regulation. Leveraging our selective CDK inhibition expertise, we discovered potent, selective, and oral CDK12 inhibitors, which affect the expression of genes involved in DNA damage response to drive anti-tumor activity," said Eric R. Olson, Ph.D., Chief Scientific Officer of Syros. "Based on the promising new data presented at AACR (Free AACR Whitepaper), in which CDK12 inhibition induced strong tumor growth inhibition and demonstrated synergies in combination with existing standard of care approaches, we believe a CDK12 inhibitor has the potential to play a key role in breast, lung, and ovarian cancer treatment. We look forward to nominating our next development candidate from our CDK12 program in the second half of this year, as we aim to address a significant unmet need for patients, including those who are resistant to DNA damaging agents or PARP inhibitors."
Preclinical Data from Oral CDK12 Inhibitor Program
Syros designed a series of CDK12 inhibitors that were profiled in biochemical and cellular assays. The data presented at AACR (Free AACR Whitepaper) detail for the first time the potency, selectivity, and anti-tumor activity from a representative member of the class, which exhibited low nanomolar potency and selectivity over CDK2, CDK7, and CDK9 of 46-, 27-, and 9-fold, respectively.
As a single agent in cancer cell models, this CDK12 inhibitor induced DNA damage, cell cycle dysregulation and genomic instability leading to growth inhibition and apoptosis. Additionally, as a single agent in in vivo cancer models this CDK12 inhibitor demonstrated tumor regressions in small cell lung cancer and breast cancer models, at well tolerated doses.
In combination in vitro, this CDK12 inhibitor showed synergistic or additive antiproliferative effects in combination with the DNA damaging agent, lurbinectedin, and the PARP inhibitor, olaparib, with increases in DNA damage and impaired DNA damage repair. In vivo, CDK12 inhibition in combination with lurbinectedin showed enhanced anti-tumor activity in a cell line derived model of small cell lung cancer, and in combination with olaparib showed enhanced anti-tumor activity in a PARP inhibitor resistant patient-derived model (PDX) of ovarian cancer.
The poster is now available on the Publications and Abstracts section of the Syros website at www.syros.com.