Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety

https://doi.org/10.1016/j.apsb.2022.02.015

In this new article publication from Acta Pharmaceutica Sinica B , authors Wei Gao, Hongxiang Hu, Lipeng Dai and colleagues from the University of Michigan, Ann Arbor, MI, USA and Bristol Myers Squibb, Summit, NJ, USA discuss how structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy and safety.

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 vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity.

In this study, the authors of this article 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 results suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. 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.

Article reference: Wei Gao, Hongxiang Hu, Lipeng Dai, Miao He, Hebao Yuan, Huixia Zhang, Jinhui Liao, Bo Wen, Yan Li, Maria Palmisano, Mohamed Dit Mady Traore, Simon Zhou, Duxin Sun, Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety, Acta Pharmaceutica Sinica B, 2022, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2022.02.015 .

Keywords: Structure‒activity-relationship (SAR); Structure-tissue exposure/selectivity relationship (STR); Drug optimization; Clinical efficacy/toxicity; Drug development

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383522000715-ga1_lrg.jpg

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association .

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CiteScore: 12.5

Impact Factor: 11.614

JIF without self-citation: 10.746

ISSN 2211-3835

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