Cyclacel’s Clinical Stage CDK2/9 Inhibitor Fadraciclib Targets Key Anti-Apoptotic and Oncogenic Pathways in Cancer
Jul 13 2020
-- Characterization of fadraciclib published in peer-reviewed journal shows specificity against
CDK2 and CDK9 and enablement of apoptosis of cancer cells driven by MCL1, cyclin E and/or MYC –
-- Data builds on growing body of evidence indicating the promise of dual CDK2/9 inhibition --
“The published findings strengthen the mechanistic rationale for fadraciclib’s potential as an anti-cancer therapy. Building upon previous research in CDK pathways, including the roles of cyclin E, MCL1 and MYC overexpression, the paper highlights the benefits of inhibiting both CDK2 and CDK9, two complementary cancer pathways,” said
“These exciting new findings revealing fadraciclib’s chemical structure and describing its relevant anti-cancer properties, reflect the highly productive collaboration of ICR with
Cyclin-dependent kinases (CDKs) exist in many isoforms and as key cell cycle regulators can play a critical role in cancer growth. This preclinical characterization of fadraciclib includes its potency and selectivity against CDK2 and CDK9 in vitro and in a broad range of cancer cell lines including AML, breast and colorectal. Further in vivo efficacy was demonstrated in leukemia xenograft models.
Experimental results support fadraciclib’s anti-cancer activity through CDK2/9 inhibition. In breast cancer cell lines, short-pulse treatment with fadraciclib showed preferential activity against transformed cells over normal cells. This finding supports the compound’s potential benefit in cancers addicted to cyclin E which can be rationally targeted by CDK2 inhibition. In AML models, fadraciclib was effective in inhibiting CDK9 and suppressing the MCL1 protein to induce apoptosis or programmed cell death of leukemia cells. Fadraciclib also demonstrated synergy with BCL2 inhibitors such as venetoclax in AML cells. In subcutaneous mouse xenograft models of AML and MLLr-AML, nearly 100% tumor growth inhibition was achieved with oral administration of fadraciclib at pharmacological doses.
Title: Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer
About Cyclin-Dependent Kinases and Fadraciclib
Cyclin-dependent kinases (CDKs) are critical for cell cycle regulation and transcriptional elongation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased survival. Fadraciclib (CYC065) is a potent orally and intravenously available inhibitor of CDK2 and CDK9. CDK9 regulates transcription of genes through phosphorylation of RNA polymerase II (RNAP II) C-terminal domain (CTD). Inhibition of CDK9 by fadraciclib suppresses CDK9-dependent gene expression and reduces the level of MCL1, a key anti-apoptotic protein.
Fadraciclib is in an ongoing Phase 1, first-in-human study in patients with advanced solid tumors. In this all-comer study, target engagement and durable suppression of the MCL1 biomarker were observed after a single dose of fadraciclib. Tumor shrinkage and stable disease were observed in five patients with cyclin E, MCL1 or MYC amplified advanced cancers. In the ongoing part 2 of the study evaluating a more intensive dosing regimen, a durable partial response has been observed in a heavily pretreated patient with MCL1-amplified endometrial cancer. Fadraciclib is also being evaluated in Phase 1 combination studies with venetoclax in relapsed or refractory CLL and in relapsed or refractory AML or MDS. Preclinical data suggest that fadraciclib may benefit patients with adult and pediatric hematological malignancies such as CLL, AML, ALL, B-cell lymphomas, multiple myeloma and certain cyclin E-addicted or MYC-amplified solid tumors, including certain forms of breast cancer, neuroblastoma, ovarian cancer and uterine serous carcinoma.
This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and intended utilization of
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