Gao Wei, Hu Hongxiang, Dai Lipeng, He Miao, Yuan Hebao, Zhang Huixia, Liao Jinhui, Wen Bo, Li Yan, Palmisano Maria, Traore Mohamed Dit Mady, Zhou Simon, Sun Duxin
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA.
Acta Pharm Sin B. 2022 May;12(5):2462-2478. doi: 10.1016/j.apsb.2022.02.015. Epub 2022 Feb 23.
Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.
药物优化通过构效关系（SAR）和类药性质来提高药物效力/特异性，其过程十分严格，目的是为临床试验筛选候选药物。然而，当前的药物优化可能忽略了疾病靶向组织与正常组织中的结构-组织暴露/选择性关系（STR），这可能会误导候选药物的选择，并影响临床疗效/毒性的平衡。在本研究中，我们使用七种结构相似、分子靶点相同且具有相似/不同药代动力学的选择性雌激素受体调节剂（SERM），研究了与观察到的临床疗效/毒性相关的STR。结果表明，药物的血浆暴露与药物在靶组织（肿瘤、脂肪垫、骨骼、子宫）中的暴露无关，而SERM的组织暴露/选择性与临床疗效/安全性相关。四种SERM的轻微结构修饰并未改变药物的血浆暴露，但改变了药物的组织暴露/选择性。七种高蛋白结合率的SERM在肿瘤中的积累高于周围正常组织，这可能是由于蛋白质结合药物的肿瘤EPR效应。这些结果表明，STR改变了药物在疾病靶向组织与正常组织中的组织暴露/选择性，从而影响临床疗效/毒性。在为临床试验选择候选药物时，药物优化需要平衡SAR和STR，以提高临床药物开发的成功率。
