PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Preclinical development of CDDD3-14, a potent and selective inhibitor of CDK4/6 for the treatment of breast cancer
Laychiluh Bantie , Solomon Tadesse , Jimma Likisa , Mingfeng Yu , Benjamin Noll , Gary Heinemann , Robert Milne , Hugo Albrecht & Shudong Wang
Drug Discovery and Development, University of South Australia Cancer Research Institute, Adelaide, Australia.
Deregulation of the CDK4/6-cyclin D-Rb-E2F pathway is common in subtypes (e.g. ER+/HER2−) of breast cancer, and activation/amplification of cyclin D1 (CCND1) and CDK4/6, or deletion/mutation of CDKN2A gene that encodes p16INK4a are the major mechanisms. Aberration in the upstream pathways such as PI3K/Akt/mTOR can also lead to the deregulation of the CDK4/6 axis, which drives carcinogenesis and development of resistance to therapies. Therefore, inhibition of CDK4/6 is a rational approach for effectively treating breast cancer. We have identified a highly potent inhibitor of CDK4/6, CDDD3-14, that showed excellent selectivity for CDK4/6 over a panel of >360 human kinases. It held the growth and proliferation of Rb-proficient cancer cell lines, including those cancers of breast, colon, prostate, pancreatic, lung and melanoma, and was more potent than palbociclib, a FDA-approved CDK4/6 inhibitor. CDDD3-14 arrested breast cancer cells in G1 phase of the cell cycle, prevented their colony formation and induced senescence. It blocked the phosphorylation of Rb protein and inhibited the E2F-transcription programs leading to reduced level of cyclins E2, A2, B1, TS and TOPOIIα. Moreover, CDDD3-14 possessed high oral bioavailability, and demonstrated marked in vivo anti-tumor efficacy in a MCF-7 breast cancer xenograft model (T/C=18%, P< 0.0001) without causing any histopathological changes to animal organs including blood, bone marrow, intestine, liver, heart and kidneys of animal. In conclusion, we have identified CDDD3-14 as a highly potent and selective inhibitor of CDK4/6 that is highly efficacious in preclinical breast tumor models. Our data suggest that CDDD3-14 is a highly promising drug candidate for the treatment of cancers.
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Oncology Abstracts
ISSN 2631-4657 (online)
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