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Cited by 1,763Computational Drug Discovery MethodsAnimal testing and alternativesStatistical Methods in Clinical Trials

The DOI matches its Crossref record; 105 of the 106 references it cites were found in a registry or an index.

Why 90% of clinical drug development fails and how to improve it?

Open access
Sun, Duxin, Gao, Wei, Hu, Hongxiang, Zhou, Simon·2022·Acta Pharmaceutica Sinica B
DOI 10.1016/j.apsb.2022.02.002PMC PMC9293739
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Abstract

Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.

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Crossref · 10.1016/j.apsb.2022.02.002

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105 of 105 references verified0 citation errors · 0 not checkable

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Graphical abstract Graphical abstract Structure‒tissue exposure/selectivity–activity relationship (STAR) selects drug candidates and balances clinical dose/efficacy/toxicity.
Graphical abstract Graphical abstract Structure‒tissue exposure/selectivity–activity relationship (STAR) selects drug candidates and balances clinical dose/efficacy/toxicity.CC BY-NC-ND · PubMed Central
Figure 1 The process of drug discovery and development, and the failure rate at each step.
Figure 1 The process of drug discovery and development, and the failure rate at each step.CC BY-NC-ND · PubMed Central
Figure 2 Structure‒tissue selectivity/exposure–activity relationship (STAR) selects better drug candidates and balances clinical dose/efficacy/toxicity to improve drug optimization for successful clinical drug development.
Figure 2 Structure‒tissue selectivity/exposure–activity relationship (STAR) selects better drug candidates and balances clinical dose/efficacy/toxicity to improve drug optimization for successful clinical drug development.CC BY-NC-ND · PubMed Central
Figure 3 In vitro high-throughput screening tool to study the structure–tissue selectivity/exposure–activity relationship (STR). (A) Tissue diffusion chamber may provide an easy and high throughput screening to study structure‒tissue exposure/selectivity relationship (STR). (B) Single-organ chips, and (C) Body-on-a-Chip integrates multiple organ units to study STR in different organs.
Figure 3 In vitro high-throughput screening tool to study the structure–tissue selectivity/exposure–activity relationship (STR). (A) Tissue diffusion chamber may provide an easy and high throughput screening to study structure‒tissue exposure/selectivity relationship (STR). (B) Single-organ chips, and (C) Body-on-a-Chip integrates multiple organ units to study STR in different organs.CC BY-NC-ND · PubMed Central
Figure 4 Implementation of structure‒tissue selectivity/exposure–activity relationship (STAR) for lead compound selection in the current drug optimization process.
Figure 4 Implementation of structure‒tissue selectivity/exposure–activity relationship (STAR) for lead compound selection in the current drug optimization process.CC BY-NC-ND · PubMed Central

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Show all 106 references

Research works printed but not linked: 3

  1. Kerns, 2008, Chapter 2—advantages of good drug-like properties, 6
  2. Kerns, 2008, Chapter 19 - pharmacokinetics, 228
  3. Wei Gao, 2022, Structure‒tissue exposure/selectivity relationship (STR) may correlate with clinical efficacy/safety, Acta Pharm Sin B

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Metadata

Authors
Sun, D., Gao, W., Hu, H., & Zhou, S.
Affiliations
  • University of Michigan (US)
  • Bristol-Myers Squibb (United States) (US)
Corresponding author
Sun, Duxin
ORCID
Venue
Acta Pharmaceutica Sinica B
Publisher
Elsevier BV
Published
2022-07
Volume
12
Issue
7
Pages
3049-3062
ISSN
2211-3835 (ISSN-L)
DOI
10.1016/j.apsb.2022.02.002
PMC
PMC9293739
OpenAlex
W4211238337
Cited by
1,763
References
106
Citations by year
2026: 482 · 2025: 550 · 2024: 456 · 2023: 230 · 2022: 45
FWCI
27.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
Keywords
medication optimization, tissue selectivity, structure-activity relationship, target validation

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