- |||||||||| BTX-9341 / BioTheryX
Discovery of BTX-9341, a bifunctional degrader of CDK4 and CDK6 for HR+/HER2- breast cancer. (Hall 2-3) - Nov 4, 2023 - Abstract #SABCS2023SABCS_1731;
These results show that BTX-9341 displays excellent single agent activity in vitro and in vivo particularly in comparison to clinically approved CDK4/6i and that this activity is maintained in CDK4/6i resistant models. This indicates that a degrader approach to targeting this pathway may be more effective than current therapies, and that using this modality in a post CDK4/6i setting may be more effective than switching CDK4/6 inhibitors.
- |||||||||| Ibrance (palbociclib) / Pfizer
Journal: Targeting Non-Kinase Function of CDK6 to Overcome CDK4/6 Inhibitor Resistance. (Pubmed Central) - Oct 3, 2023
Our studies show that non-kinase function of CDK6 plays a critical role in palbociclib resistance. We also provide a novel therapeutic strategy to overcome CDK4/6 inhibitor resistance, thereby setting the stage for development of next generation drugs that eliminate both the kinase and non-kinase functions of this class of proteins.
- |||||||||| Ibrance (palbociclib) / Pfizer
Targeting Non-Kinase Function of CDK6 to Overcome CDK4/6 Inhibitor Resistance (Room 30 D/E) - Aug 22, 2023 - Abstract #ASTRO2023ASTRO_816;
Our studies show that non-kinase function of CDK6 plays a critical role in palbociclib resistance. We also provide a novel therapeutic strategy to overcome CDK4/6 inhibitor resistance, thereby setting the stage for development of next generation drugs that eliminate both the kinase and non-kinase functions of this class of proteins.
- |||||||||| Ibrance (palbociclib) / Pfizer
Journal: Development of PROTAC degrader probe of CDK4/6 based on DCAF16. (Pubmed Central) - Jul 10, 2023
Moreover, the toxicity of A4 in normal cells showed 7 times lower than that of Palbociclib, and A4 exhibits therapeutic potential in MDA-MB-231 xenograft models in vivo. These findings indicate that A4, as a novel CDK4/6 degrader based on DCAF16, is worthy of further investigating for the treatment of TNBC.
- |||||||||| Ibrance (palbociclib) / Pfizer, Kisqali (ribociclib) / Novartis
Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer. (On Demand | Hall A; Poster Bd # 304) - Apr 26, 2023 - Abstract #ASCO2023ASCO_3275;
Background: CDK4/6 inhibitors (CDK4/6i) such as palbociclib and ribociclib are used to treat ER+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on the upregulation of CDK6. Our CDK4/6 bifunctional degraders display excellent single agent activity in vitro and in vivo particularly in comparison to clinically approved CDK4/6i, indicating that using a degrader approach to targeting this pathway may be more effective than current inhibitor therapies.
- |||||||||| Ibrance (palbociclib) / Pfizer
Journal: SETDB1 modulates degradation of phosphorylated RB and anti-cancer efficacy of CDK4/6 inhibitors. (Pubmed Central) - Mar 16, 2023
However, coadministration of the CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both in vitro and in vivo...This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for treatment of cancers with SETDB1 gene amplification or overexpression.
- |||||||||| DKY709 / Novartis, Ibrance (palbociclib) / Pfizer
Journal: Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios. (Pubmed Central) - Sep 20, 2022
Pharmacological codegradation of CDK4/6 and Helios resulted in potent suppression of downstream signaling and proliferation in cancer cells, as well as enhanced derepression of IL-2 secretion. Thus, not only do we demonstrate the possibility of rationally redirecting the neo-substrate specificity of PROTACs by incorporating alternative molecular glue molecules as E3 ligase ligands but our findings also suggest that cotargeting CDK4/6 and Helios may have synergistic effects.
|
