Targeting the unactivated conformations of protein kinases for small molecule drug discovery

Alton, Gordon; Lunney, Elizabeth A.

doi:10.1517/17460441.3.6.595

Cited by 30 publications

(21 citation statements)

References 87 publications

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“…Note that imatinib is known to bind to spleen tyrosine kinase (SYK) in an orientation that is different from that observed for Bcr-Abl and other tyrosine kinases (Alton and Lunney, 2008 ). A crystal structure of the imatinib-SYK complex exists (1XBB; Atwell et al, 2004 ) but is not part of the Sperrylite Dataset because of a poor electron density support of parts of the ligand facing the bulk water phase (Figure S2 ).…”

Section: Resultsmentioning

confidence: 96%

How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?

2018

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Knowledge of the bioactive conformations of small molecules or the ability to predict them with theoretical methods is of key importance to the design of bioactive compounds such as drugs, agrochemicals, and cosmetics. Using an elaborate cheminformatics pipeline, which also evaluates the support of individual atom coordinates by the measured electron density, we compiled a complete set (“Sperrylite Dataset”) of high-quality structures of protein-bound ligand conformations from the PDB. The Sperrylite Dataset consists of a total of 10,936 high-quality structures of 4,548 unique ligands. Based on this dataset, we assessed the variability of the bioactive conformations of 91 small molecules—each represented by a minimum of ten structures—and found it to be largely independent of the number of rotatable bonds. Sixty-nine molecules had at least two distinct conformations (defined by an RMSD greater than 1 Å). For a representative subset of 17 approved drugs and cofactors we observed a clear trend for the formation of few clusters of highly similar conformers. Even for proteins that share a very low sequence identity, ligands were regularly found to adopt similar conformations. For cofactors, a clear trend for extended conformations was measured, although in few cases also coiled conformers were observed. The Sperrylite Dataset is available for download from http://www.zbh.uni-hamburg.de/sperrylite_dataset.

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Section: Resultsmentioning

confidence: 96%

How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?

2018

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“…The rationale for harnessing selective interactions targeting DFG out is based on binding in the RDP, away from conserved regions of the ATP site (12,27). However, the structurally diverse VEGFR TKIs, most of which do not occupy the RDP, all bind the DFG out conformation.…”

Section: Discussionmentioning

confidence: 99%

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

McTigue

Murray

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

424

282

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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 ) 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.T he VEGF receptor (VEGFR) tyrosine kinases (TKs) are the clinically validated drug target of four structurally diverse TK inhibitors (TKIs) that have been approved in the renal cell carcinoma (RCC) setting (1, 2). The clear cell histology subtype of RCC is molecularly linked to the VEGF signaling axis by virtue of the ∼90% incidence of Von Hippel-Lindau (VHL) dysregulation. With VHL inactivation, hypoxia-inducible factor-α accumulates, leading to overproduction of the angiogenic factor VEGF among others. It is, therefore, generally accepted that on-target VEGFR TK inhibition accounts for the RCC efficacy seen within this class of TKIs. In addition to efficacy in RCC, VEGF signaling inhibition has been linked to side effects, with the most prominent being hypertension, which is consistently seen within the TKI class and the related monoclonal antibody to VEGF, bevacizumab (3).Despite the clear role of VEGF signaling on both hypertension and efficacy in RCC, these on-target pharmacologic effects differ in frequency and degree between approved VEGFR TKI drugs, indicating that the extent of VEGF signal blockade may not be equivalent. Recent reports have analyzed similar RCC clinical studies across leading VEGFR TKIs for comparison purposes (1, 2). Clear distinction in both efficacy...

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“…One potential way to mitigate issues related to kinome selectivity is to target the inactive form of the kinase. When targeting the inactive form of a kinase, both ATP competitive and noncompetitive binders can be found targeting Type II, III, or IV pockets. − In addition to affecting kinome selectivity, kinase inhibitors targeting inactive conformations may differ from Type I inhibitors in other ways. Enhanced residence times are common in non-Type I inhibitors .…”

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confidence: 99%

Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage

Hart

Abell

Guo

et al. 2019

ACS Med. Chem. Lett.

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Necroptosis has been implicated in a variety of disease states, and RIPK3 is one of the kinases identified to play a critical role in this signaling pathway. In an effort to identify RIPK3 kinase inhibitors with a novel profile, mechanistic studies were incorporated at the hit triage stage. Utilization of these assays enabled identification of a Type II DFG-out inhibitor for RIPK3, which was confirmed by protein crystallography. Structure-based drug design on the inhibitors targeting this previously unreported conformation enabled an enhancement in selectivity against key off-target kinases.

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Targeting the unactivated conformations of protein kinases for small molecule drug discovery

Cited by 30 publications

References 87 publications

How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?

How Diverse Are the Protein-Bound Conformations of Small-Molecule Drugs and Cofactors?

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

Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage

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