Mechanistic Rationale for CYC065, Cyclacel’s CDK2/9 Inhibitor, in Targeted Solid Tumors and Hematological Malignancies Presented at AACR-NCI-EORTC International Conference

On November 09, 2015 Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) ("Cyclacel" or the "Company"), reported the presentation of preclinical data demonstrating the mechanistic rationale for the development of CYC065 in targeted solid tumors and leukemias (Press release, Cyclacel, NOV 9, 2015, View Source [SID:1234508106]). CYC065 is a highly-selective, second-generation cyclin dependent kinase (CDK) inhibitor targeting CDK2- and CDK9-dependent tumors. The data were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place November 5-9, 2015, in Boston.

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"Through our understanding of the mechanism of action of CYC065 we have identified CDK2- and CDK9-dependent tumors against which CYC065 is predicted to have activity," said Spiro Rombotis, Cyclacel’s President and Chief Executive Officer. "These cancer types include hematological cancers, such as MLL-rearranged (MLLr) leukemias, MYC-driven lymphomas or solid tumors, and also cancers in which Cyclin E amplification is observed, such as drug resistant and poor prognosis breast and uterine cancers. In addition, we have identified approved and investigational anticancer agents, including our own sapacitabine, which exhibit a synergistic effect when combined with CYC065. A first-in-human, Phase 1 clinical trial with CYC065 has commenced and we look forward to reporting data from this study."

Data presented at AACR (Free AACR Whitepaper)-NCI-EORTC (Poster no. B182) demonstrated the mechanistic rationale for clinical development of CYC065 in oncology. Relevant solid tumor and hematologic malignancies were identified, including those with amplification or overexpression of Cyclin E (the partner of CDK2), those driven by CDK9-dependent oncogenic and leukemogenic pathways, such as acute leukemias driven by MLLr and MYC overexpressing tumors. Clinically relevant synergistic combinations were identified and the mechanism of action of CYC065 as a single agent elucidated. The anticancer activity of CYC065 was evaluated in in vitro assays of human acute myelogenous leukemia (AML) and triple negative breast cancer (TNBC) cell lines to demonstrate the pro-apoptotic mechanism of CYC065 and determinants of cellular sensitivity. CYC065 induced rapid apoptosis by inhibition of expression of CDK9-dependent oncogenic transcripts, including MCL-1 and MYC. CYC065’s potent anticancer activity was confirmed in AML xenograft animal models.

CYC065 was highly synergistic in combination with Bcl-2 inhibitors, such as venetoclax (ABT-199/GDC-0199), in both AML and acute lymphoblastic leukemias. CYC065 was also synergistic in combination with Cyclacel’s sapacitabine in breast cancer cell lines, as was the case with seliciclib, Cyclacel’s first generation CDK2/9 inhibitor.

An oral regimen of seliciclib and sapacitabine is being evaluated in an on-going Phase 1 study of patients with Homologous Recombination (HR) repair-deficient breast, ovarian and pancreatic cancers, including BRCA positive tumors. CYC065 is in a first-in-human, Phase 1 clinical trial.