BGB-43395 is a potent, selective, oral CDK4 inhibitor designed to maximize sustained CDK4 pathway suppression while sparing CDK6 with the goal of improving efficacy and tolerability in HR+/HER2- breast cancer and other CDK4-dependent malignancies.1,2
In preclinical studies, BGB-43395 demonstrated CDK4 potency, robust pharmacodynamic target engagement, and strong antitumor activity, including in models resistant to CDK4/6 inhibitors, and is currently being evaluated clinically as monotherapy and in combination with endocrine therapy (NCT06120283).1
Key preclinical findings include1:
Safety and efficacy have not been established for investigational products and/or uses. The clinical relevance of nonclinical data has not been established.
CDK4, cyclin-dependent kinase 4; CDK6, cyclin-dependent kinase 6; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; IC50, half-maximal inhibitory concentration; pRB1, phosphorylated retinoblastoma protein 1; (RB1, retinoblastoma protein 1.
CDK4 and CDK6, in complex with cyclin D, are key regulators of the G1/S cell cycle transition, phosphorylating the Rb to release E2F transcription factors and drive cell cycle progression.1
Treatment with CDK4/6 inhibitors and endocrine therapy has improved outcomes in HR+/HER2- breast cancer.2 However, dual CDK4/6 inhibitors (eg, palbociclib, ribociclib, abemaciclib) are associated with dose-limiting neutropenia, often requiring treatment interruptions or dose reductions that limit sustained CDK4/6 suppression.3
Neutropenia is associated with CDK6 inhibition as CDK6 has additional roles as a transcriptional regulator and activator of hematopoietic stem cells (HSCs).1 Selective CDK4 inhibition may be a way to avoid this adverse event.
BGB-43395 selectively inhibits CDK4/cyclin D activity, leading to potent suppression of Rb phosphorylation, induction of G1 cell cycle arrest, and cellular senescence in CDK4-dependent tumor cells in vitro.4
CDK4, cyclin-dependent kinase 4; CDK6, cyclin-dependent kinase 6; E2F, eukaryotic transcription factor family; HER2-, human epidermal growth factor receptor 2 negative; HR+, hormone receptor positive; HSC, hematopoietic stem cell; Rb, retinoblastoma protein.
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