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

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

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,


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


Graphical Abstract: available at

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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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