Impact of structural biology and the protein data bank on us fda new drug approvals of low molecular weight antineoplastic agents 2019–2023

Abstract Open access to three-dimensional atomic-level biostructure information from the Protein Data Bank (PDB) facilitated discovery/development of 100% of the 34 new low molecular weight, protein-targeted, antineoplastic agents approved by the US FDA 2019–2023. Analyses of PDB holdings, the scien...

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Bibliographic Details
Published in:Oncogene 2024-07, Vol.43 (29), p.2229-2243
Main Authors: Burley, Stephen K., Wu-Wu, Amy, Dutta, Shuchismita, Ganesan, Shridar, Zheng, Steven X. F.
Format: Article
Language:English
Subjects:
Abl protein
Antineoplastic drugs
BCR protein
Data banks
Drug delivery
Drug discovery
Enzyme inhibitors
Fusion protein
Helix-loop-helix proteins (basic)
Kinases
Methyltransferase
Molecular weight
Nuclear transport
Protein-tyrosine kinase receptors
Proteins
Review
Therapeutic targets
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Summary:Abstract Open access to three-dimensional atomic-level biostructure information from the Protein Data Bank (PDB) facilitated discovery/development of 100% of the 34 new low molecular weight, protein-targeted, antineoplastic agents approved by the US FDA 2019–2023. Analyses of PDB holdings, the scientific literature, and related documents for each drug-target combination revealed that the impact of structural biologists and public-domain 3D biostructure data was broad and substantial, ranging from understanding target biology (100% of all drug targets), to identifying a given target as likely druggable (100% of all targets), to structure-guided drug discovery (>80% of all new small-molecule drugs, made up of 50% confirmed and >30% probable cases). In addition to aggregate impact assessments, illustrative case studies are presented for six first-in-class small-molecule anti-cancer drugs, including a selective inhibitor of nuclear export targeting Exportin 1 (selinexor, Xpovio), an ATP-competitive CSF-1R receptor tyrosine kinase inhibitor (pexidartinib,Turalia), a non-ATP-competitive inhibitor of the BCR-Abl fusion protein targeting the myristoyl binding pocket within the kinase catalytic domain of Abl (asciminib, Scemblix), a covalently-acting G12C KRAS inhibitor (sotorasib, Lumakras or Lumykras), an EZH2 methyltransferase inhibitor (tazemostat, Tazverik), and an agent targeting the basic-Helix-Loop-Helix transcription factor HIF-2α (belzutifan, Welireg).
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-024-03077-2