RESUMEN
Zanubrutinib an oral irreversible Bruton's tyrosine kinase (BTK) inhibitor, is under development for the treatment of a variety of B-cell malignancies and has received accelerated approval by the US Food and Drug Administration for treatment of adult patients with mantel cell lymphoma who have received at least one prior therapy. Zanubrutinib moderately inhibited the human ether- à -go-go-related gene channel with half maximal inhibition concentration (IC50) of 9.11 µM and showed neither effects on the cardiovascular system functions in telemetry-implanted dogs nor on the respiratory and central nervous system functions in rats. No toxicologically significant changes were noted in rats and dogs at the systemic exposure ratios (area under the curve ratio between animals and humans at the therapeutic dose) up to 26- and 15-fold for 26-weeks and 39-weeks of treatment, respectively. Zanubrutinib was not genotoxic. Fertility studies showed no abnormal findings in both male and female rats at the systemic exposure ratios of up to 12-fold; embryo-fetal studies showed no fetal lethality or teratogenicity in rabbit or rat fetuses at the systemic exposure ratios of up to 25- and 16-fold, respectively, except for 0.3% to 1.5% of 2 or 3 chambered hearts in rat fetuses; pre- and postnatal developmental toxicity showed no effects in rats at the systemic exposure ratios up to 16-fold except for an increased incidence (26% to 42%) and severity of various ophthalmic lesions in treated groups compared to the concurrent control group (26%). These nonclinical study results suggest that zanubrutinib has a broad safety window and an optimal safety profile while treating patients with advanced cancers.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antineoplásicos/toxicidad , Piperidinas/toxicidad , Inhibidores de Proteínas Quinasas/toxicidad , Pirazoles/toxicidad , Pirimidinas/toxicidad , Animales , Antineoplásicos/farmacología , Perros , Desarrollo Embrionario/efectos de los fármacos , Femenino , Desarrollo Fetal/efectos de los fármacos , Masculino , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Conejos , Ratas , Reproducción/efectos de los fármacos , Pruebas de ToxicidadRESUMEN
Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035 is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to that of BGB-3111.