Great achievements have been announced for CDK4/6 inhibitors in many clinical studies and these encouraging results have prompted clinicians to change treatment paradigms for metastatic HR+/HER2 − breast cancers. At present, three orally bioavailable CDK4/6 inhibitors, palbociclib (Ibrance, PD0332991; Pfizer, New York, NY, USA), ribociclib (Kisqali, LEE011; Novartis, Basel, Switzerland), and abemaciclib (Verzenio, LY2835219; Eli Lilly and Company, Indianapolis, IN, USA), have been approved by the United States Food and Drug Administration for treatment of patients with HR+/HER2 − metastatic breast cancer [18, 19]. These CDK4/6 inhibitors can be administered as monotherapy in heavily pretreated patients, as combination therapy with aromatase inhibitors for initial therapy, or as combination therapy with fulvestrant after disease progression following first-line endocrine therapy. However, because these drugs are expensive or unavailable to patients in China, development of new CDK4/6 inhibitors with improved efficacy and reduced toxicity is urgently needed in China.
In this study, BPI-16350, a novel CDK4/6 inhibitor developed by the Chinese pharmaceutical company Betta Pharmaceutical (Zhejiang, China), was shown to exhibit potent antitumor activity both in vivo and in vitro. BPI-16350, which exhibited strong kinase selectivity comparable to abemaciclib, inhibited the proliferation and viability of Rb-positive cancer cell lines by inducing cell cycle arrest in G1 phase. In xenograft models, BPI-16350 administration could suppress tumor growth in a dose-dependent manner. Importantly, BPI-16350 exhibited favorable pharmacokinetic and pharmacodynamic properties without causing noticeable toxicity in animal models. Our results also demonstrate that combination therapy with fulvestrant yielded greater inhibition of proliferation than individual treatment in cancer cell lines similar with previous studies [20, 21]. The potent anti-tumor activity and enhanced characteristics revealed by our experiments provide a strong rationale for ongoing clinical trials of BPI-16350. Indeed, we observed clinical benefit and better tolerance during period of dose escalation in a phase I clinical trial of one PR.
In previous studies, abemaciclib was reported to be structurally different from palbociclib and ribociclib, and demonstrated stronger (nanomolar) selectivity for CDK4 and CDK6 . BPI-16350 has a similar structure (data not shown) and better selectivity towards CDK4/cyclin D1 and CDK6/cyclin D1 compared with abemaciclib. Notably, BPI-16350 had a weaker effect on other CDKs compared with abemaciclib, especially CDK9, for which abemaciclib is a potent inhibitor [23, 24]. Inhibition of CDK9 can modify the glycogen synthase kinase 3-mediated effects of abemaciclib, leading to observations of specific intestinal toxicity [24–26]. Thus, it is predicted that BPI-16350 may have fewer intestinal reactions, such as diarrhea and nausea. Indeed, in an ongoing phase I study, BPI-16350 elicited controllable diarrhea less than or equivalent to grade I CTCAE5.0 in a majority of subjects, which may be explained by its lack of inhibition for CDK9. We also observed substantially lower incidence and severity of myelotoxicity following continuous dose scheduling of BPI-16350, which is not achieved with 1-week drug holiday of palbociclib or ribociclib [27, 28]. Moreover, oral administration of BPI-16350 is more convenient (once a day) than abemaciclib (twice a day) to reach an effective biological dose. Consistent with the preclinical results, detected concentrations of BPI-16350 were lower in plasma, tumor, and brain following twice-daily compared with once-daily administration at the same total dosage.
A distinct feature of abemaciclib is its ability to cross the BBB; fortunately, because of its similar molecular structure, BPI-16350 exhibits BBB permeability in rodents. Breast cancer brain metastasis, one of the most common forms of breast cancer metastasis, has a poor prognosis [29, 30]. In a comparative study of breast cancers with brain metastasis, median overall patient survival was 7.1 months for HR+/HER2−, 18.9 months for HR+/HER2+, 13.1 months for HER2−, and 4.4 months for triple-negative forms . The poor prognosis after brain metastasis may result from the BBB removing drug substances such as chemotherapeutic agents, targeted agents, and toxins from the brain [32, 33]. The BBB is constructed of specialized blood vessel structures comprising endothelial cells, astrocytes, pericytes, and neurovascular units . Endothelial cells express several transporters (e.g., P-glycoprotein and multidrug-resistance proteins) that act as efflux pumps [35, 36]. Our exploratory results indicate that BPI-16350 has high permeability in Caco-2 cells and, although less obvious, appears a less likely substrate for efflux compared with P-glycoprotein and breast cancer resistance protein; moreover, BPI-16350 had a certain inhibitory effect on these proteins. Importantly, BPI-16350 was observed to have a six-fold brain-to-plasma ratio following 100 mg/kg administration in mice, indicating high brain-penetration potential. Consistent with preclinical results, a phase I study of BPI-16350 in patients with breast cancer brain metastasis revealed that all extracranial lesions were regrade and intracranial multiple lesions were continually stable without out of group. However, more evidence is needed to establish whether BPI-16350 influences and permeates the BBB.
In conclusion, BPI-16350 is a potent and orally available CDK4/6 inhibitor with broad-spectrum anti-tumor effects against Rb-positive cancer cell lines. Moreover, BPI-16350 exhibited feasibility, antitumor efficacy, higher safety, and a high degree of BBB permeability indicating great potential for the treatment of brain metastases and tumors of the central nervous system.