This research describes the portrayal of the novel kinase inhibitor, ON123300, which inhibits CDK4/6 (cyclin-dependent kinases 4 and 6) and phosphatidylinositol 3 kinase-|? (PI3K-|?) and exhibits potent activity against mantle cell lymphomas (MCLs) in vitro as well as in vivo. We examined the results of PD0332991 and ON123300 on cell cycle progression, modulation from the retinoblastoma (Rb) and PI3K/AKT pathways, and also the induction of apoptosis in MCL cell lines and patient-derived samples. When Granta 519 and Z138C cells were incubated with PD0332991 and ON123300, both compounds were equally efficient within their capability to hinder the phosphorylation of Rb family proteins. However, only ON123300 inhibited the phosphorylation of proteins connected using the PI3K/AKT path. Cells given PD0332991 quickly accrued within the G0/G1 phase of cell cycle like a purpose of growing concentration. Although ON123300-treated cells arrested similarly at lower concentrations, greater concentrations led to the induction of apoptosis, that was not noticed in PD0332991-treated samples. Mouse xenograft assays also demonstrated a powerful inhibition of MCL tumor development in ON123300-treated creatures. Finally, management of ibrutinib-sensitive and -resistant patient-derived MCLs with ON123300 also triggered apoptosis and inhibition from the Rb and PI3K/AKT pathways, suggesting this compound may be a highly effective agent in MCL, including ibrutinib-resistant types of the condition.