Rathi Sneha, Oh Ju-Hee, Zhang Wenjuan, Mladek Ann C, Garcia Darwin A, Xue Zhiyi, Burgenske Danielle M, Zhang Wenqiu, Le Jiayan, Zhong Wei, Sarkaria Jann N, Elmquist William F
Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.)
Brain Barriers Research Center, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (S.R., J.-H.O., W.J.Z., W.Q.Z., J.L., W.F.E.); Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (A.C.M., D.A.G., Z.X., D.M.B., J.N.S.); and WayShine Biopharm, Shanghai, China (W.Z.).
J Pharmacol Exp Ther. 2024 Jul 18;390(2):260-275. doi: 10.1124/jpet.123.001971.
Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.
放射治疗是许多癌症患者的标准治疗选择，它会诱导DNA双链断裂（DSB），从而导致细胞死亡。共济失调毛细血管扩张症突变（ATM）激酶是DSB修复的关键调节因子，ATM抑制剂正在作为各种肿瘤（包括原发性和转移性脑肿瘤）的放射增敏剂进行研究。脑肿瘤放射增敏剂的疗效可能会受到血脑屏障缺乏有效药物递送的影响。本研究的目的是评估新型强效ATM抑制剂WSD0628在小鼠体内的全身药代动力学以及影响其在中枢神经系统（CNS）分布的机制。此外，我们利用这些观察结果为预测临床应用的有效暴露量奠定基础。我们观察到暴露量的增加大于剂量比例，这可能是由于清除过程的饱和所致。我们的结果表明，WSD0628具有口服生物利用度且可穿透中枢神经系统，其在中枢神经系统中的未结合分配（即未结合组织分配系数）在0.15至0.3之间。中枢神经系统分布不受外排转运蛋白P-糖蛋白和乳腺癌耐药蛋白的限制。WSD0628在不同脑区均匀分布。因此，WSD0628具有良好的药代动力学特性，有进一步探索以确定其在中枢神经系统肿瘤中的药效学-药代动力学疗效关系的潜力。这种方法将为WSD0628用于治疗原发性和继发性脑肿瘤的临床转化提供关键见解。意义声明：本研究评估了新型ATM抑制剂WSD0628用于治疗脑肿瘤的临床前全身药代动力学、剂量比例以及影响其在中枢神经系统分布的机制。结果表明，WSD0628具有口服生物利用度且可穿透中枢神经系统，不存在外排转运蛋白相关问题。我们还观察到血浆和脑中的暴露量增加大于剂量比例。这些良好的药代动力学特性表明WSD0628有进一步探索用作脑肿瘤治疗放射增敏剂的潜力。
