On March 7, 2017 Cyclacel Pharmaceuticals, Inc. (Nasdaq:CYCC) (Nasdaq:CYCCP) ("Cyclacel" or the "Company"), reported the publication of a peer-reviewed journal article featuring the company’s cyclin dependent kinase 2/9 (CDK2/9) inhibitors (Press release, Cyclacel, MAR 7, 2017, View Source [SID1234518016]). In an article published in the Journal of National Cancer Institute (JNCI), preclinical data demonstrated that both Cyclacel’s CYC065, a second-generation, clinical stage, CDK2/9 inhibitor, and CCT68127, a pre-clinical stage CDK2/9 inhibitor, demonstrated prominent antitumor activity against lung cancer through anaphase catastrophe, a novel, cancer specific mechanism of action. Schedule your 30 min Free 1stOncology Demo! The Journal of National Cancer Institute article entitled, "Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer," demonstrates that CYC065 and CCT68127 cause multipolar anaphase and apoptosis in lung cancer cells with supernumerary centrosomes, known as anaphase catastrophe. This novel mechanism of action offers an innovative approach to combat aneuploid cancer cells which contain abnormal numbers of chromosomes. Aneuploidy is a hallmark for cancer development and occurs in virtually every cancer, but is particularly found in lung cancer. Approximately 90 percent of cancer cells in solid tumors and blood cancer are aneuploid.
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The article further reported that inhibition of CDK2 was the key mechanism of action and, as a consequence, lung cancer cells underwent apoptosis or cell suicide by induction of a novel mechanism called anaphase catastrophe. Similarly to a previous report on seliciclib (Cyclacel’s first generation CDK inhibitor), lung cancer cells with mutant KRAS were particularly sensitive to CYC065 and CCT68127. Combination of CCT68127 with the MEK inhibitor, trametinib, was synergistic. An efficacy study in syngeneic cancer models of lung cancer with mutant KRAS demonstrated tumor growth inhibitory effect and a significant decrease of circulating tumor cells.
Citation:
Kawakami M, Lisa, Mustachio M, Rodriguez-Canales J, Mino B, Roszik J, Tong P, Wang J, J. Lee J, Myung JH, Heymach JV, Johnson FM, Hong S, Zheng L, Hu S, Villalobos PA, Behrens C, Wistuba I, Freemantle S, Liu X, Dmitrovsky E. Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer. J Natl Cancer Inst (2017) 109(6): djw297.
About CYC065
Cyclacel’s second generation CDK2/9 inhibitor, CYC065, is being evaluated in an ongoing, first-in-human, Phase 1 trial in patients with advanced solid tumors. In addition to determining safety and recommended dosing for Phase 2, the study aims to investigate CYC065’s effects on the Mcl-1 biomarker, which is implicated in the evolution of resistance in cancer. Evidence of target engagement with prolonged Mcl-1 suppression in peripheral blood cells was observed in patient samples from the study, as well as decreases in kinase substrate phosphorylation and increases in PARP cleavage, which were consistent with the Company’s preclinical data. CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, and improved metabolic stability than seliciclib, Cyclacel’s first generation CDK inhibitor. Similar to palbociclib, the first CDK inhibitor approved by FDA in 2015, CYC065 may be most useful as a therapy for patients with both liquid and solid tumors in combination with other anticancer agents, including Bcl-2 antagonists, such as venetoclax, or HER2 inhibitors, such as trastuzumab.