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Cited by 592

The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.

Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors

Open access
McTigue, Michele, Murray, Brion William, Chen, Jeffrey H., Deng, Ya-Li, Solowiej, James, Kania, Robert S.·2012·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1207759109
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Abstract

Analyses of compounds in clinical development have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance [Rini BI, et al. (2011) Lancet 378:193–1939]. To elucidate how fundamental drug potency–efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug–kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug–kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. The identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.

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Metadata

Authors
McTigue, M., Murray, B. W., Chen, J. H., Deng, Y.-L., Solowiej, J., & Kania, R. S.
Venue
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Published
2012-09-05
Volume
109
Issue
45
Pages
18281-18289
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1207759109
OpenAlex
W2063544208
Cited by
592
References
36
FWCI
7.67
Type
journal article
Language
en
Open access
green

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CoChat. (2026). Citation check: Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. https://app.cochat.ai/papers/10.1073/pnas.1207759109
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McTigue, M., Murray, B. W., Chen, J. H., Deng, Y.-L., Solowiej, J., & Kania, R. S. (2012). Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1207759109

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