On November 13, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported preclinical data on SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, showing synergistic anti-tumor activity in combination with carboplatin, a standard-of-care therapy, in models of ovarian cancer and providing a mechanistic rationale for the ongoing investigation of the combination in the Phase 1 clinical trial of SY-1365 (Press release, Syros Pharmaceuticals, NOV 13, 2018, View Source [SID1234531258]). The Company also announced the first preclinical data on its class of highly selective oral CDK7 inhibitors, which showed significant anti-proliferative activity in preclinical models of breast and ovarian cancers. These data were presented at the 30th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium in Dublin.

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"Selective CDK7 inhibition represents a potentially transformative approach for treating a range of cancers that have eluded effective treatment," said Eric R. Olson, Ph.D., Syros’ Chief Scientific Officer. "Our presentations at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) meeting highlight our leadership in the field and support the ongoing clinical development of SY-1365 as well as the selection of SY-5609, a highly selective oral CDK7 inhibitor, as our next development candidate. Given the broad potential of CDK7 inhibitors as a new class of medicines, we believe physicians and patients will seek options across multiple modalities and believe an oral molecule could serve as an important complement to SY-1365. We are committed to maximizing the potential of CDK7 inhibition for patients, as we work to achieve our vision of developing new medicines that provide profound benefit for patients."

SY-1365 Preclinical Combination Data
The preclinical data presented at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) provide a strong mechanistic rationale for the ongoing clinical investigation of SY-1365 in combination with carboplatin in ovarian cancer patients. Homologous recombination deficiency (HRD), a cellular defect caused by the disruption of normal DNA damage repair processes, sensitizes cells to treatment with DNA repair inhibitors, including PARP inhibitors and DNA-damaging agents such as carboplatin. In preclinical models of ovarian cancer, SY-1365 was shown to inhibit DNA repair and decrease the expression of homologous recombination repair (HRR) genes, which are important for repairing harmful breaks in DNA. These data suggest that SY-1365 induces an HRD-like state, which may result in enhanced sensitivity to DNA-damaging agents and DNA repair inhibitors.

Consistent with the proposed mechanism-of-action, SY-1365 demonstrated synergy with carboplatin in ovarian cancer cell lines and demonstrated greater anti-tumor activity in combination with carboplatin in xenograft models of ovarian cancer than either agent alone.

Syros is currently conducting a Phase 1 clinical trial assessing the safety and efficacy of SY-1365 as a single agent and in combination with standard-of-care therapies in multiple ovarian and breast cancer patient populations. The ongoing trial includes a study cohort evaluating SY-1365 in combination with carboplatin in ovarian cancer patients who have relapsed after one or more prior therapies. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov.

Preclinical Data from Oral CDK7 Inhibitor Program
Syros created a suite of highly selective and potent orally available CDK7 inhibitors. The preclinical data at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) detail for the first time the selectivity, potency and anti-tumor activity of these inhibitors. Using a representative member of Syros’ suite of oral CDK7 inhibitors, these data show:

200- to 1,200-fold greater selectivity for CDK7 over other members of the CDK family, including CDK2, CDK9 and CDK12.
Robust anti-proliferative activity in triple negative breast cancer and ovarian cancer cell lines, which was associated with the induction of apoptosis and cell cycle arrest.
Strong correlation between biochemical potency, CDK7 target engagement and tumor growth inhibition.
Substantial anti-tumor effects in multiple cell-line and patient-derived xenograft models of triple negative breast and ovarian cancers.
These data helped support the selection of SY-5609 as the Company’s next development candidate. Syros is currently advancing SY-5609 into Investigational New Drug (IND) application-enabling preclinical studies.

The poster presentations on the SY-1365 preclinical combination data and on the oral CDK7 inhibitor program are now available on the Publications and Abstracts section of the Syros website at www.syros.com.