A preclinical toxicology and pharmacology study of OQL051, a gut-restricted CDK4/6 inhibitor for the prophylaxis of chemotherapy-induced diarrhea

Background: Chemotherapy-induced diarrhea (CID) from fluorouracil (5FU) and irinotecan (IRI, rate 50–80%) leads to therapy interruption/discontinuation disruption of the intestinal microbiome. Cyclin-dependent kinase 4/ 6 inhibitors (CDK4/6i) induce a “pharmacological quiescence” with transient dosing. OQL051, gut-restricted CDK4/6i, decreases chemotherapy-induced histological damage wall reduces CID. We studied OQL051’s toxicology, maintenance microbiome, impact on tumor growth. Methods: Rats, 20 female, male, 6–7 weeks age were for 8 days. OQL051 was orally administered once daily (100, 250, or 500 mg/kg) 7 Mortality, clinical observations, body weight, food consumption recorded during treatment. Hematology, coagulation, serum chemistry, gross pathology, histopathological examination (14 tissue/organ panel including stomach, duodenum, jejunum, colon) conducted at D8. Blood collected 3 5 animals D1 D7 predose, 0.25, 1, 2, 4, 8, 24 h post-dose determine concentration OQL051. BALB/c mice subcutaneously injected 106 CT-26 cells (undifferentiated colon carcinoma cell line), given oral (25 control (CON) vol. 30∼50 mm3, then later, 70 mg/kg)/IRI-CON. At 200∼400 mm3 anti-PD-1 mAb (200 μg)/mAb-CON. Tumor determined routinely calipers. The GI tract sampled microbiome analysis. Microbiome DNA library (NEBNext® Ultra™ II Kit) used sequencing an Illumina NovaSeq platform. Results: No drug-related mortality adverse events (AEs) observed across all dose levels. One female rat had intussusception event 250 mg/kg; however, no abnormality observed. Compared vehicle doses showed effect intake, hematology, examination. In particular, being concentrated in gut changes colon. diversity maintained OQL051- vs. CON-treated mice, volume less OQL051+IRI+anti-PD-1 CON+IRI+anti-PD-1 (p = 0.035 @ 28 days). Conclusion: safety confirmed as there AEs repeat up mg/kg/day CDK 4/6 inhibitor common (neutropenia, leukopenia, thrombocytopenia, anemia, diarrhea, nausea, ALT) absent indicating low systemic exposure. previously decrease CID chemotherapy led potentially enhanced efficacy plus immunotherapy antitumor reducing volume. Conflict interest: Ownership: Shiyi Zhang, Founder, CEO Jie Lou, Co-founder, CSO Hong Tang, CMO Other Substantive Relationships: Wenqin Zeng, employee; Wenxi Li, Shilan Liu, Liping Chen, Robert Tyler, employee.