Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors

Damghani, Tahereh; Wittlinger, Florian; Beyett, Tyler S.; Eck, Michael J.; Laufer, Stefan; Heppner, David E.

doi:10.1016/bs.mie.2023.03.013

Cited by 3 publications

(3 citation statements)

References 63 publications

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“…Patients acquire resistance to osimertinib through several routes, most notably when the EGFR kinase domain mutates the cysteine to a serine (C797S), which is incompatible with the molecule's covalent bond forming Michael acceptor group. 26,27 While efforts are currently underway to address C797S and other modes of osimertinib-induced drug resistance, 28,29 drug development has continued to optimize third-generation compounds, such as the recently emerged YH25448 (lazertinib) 30,31 to improve various pharmacological properties (e.g., dose-limiting toxicity). Given the continued activity around optimizing irreversible EGFR TKIs it is important to properly understand the structural differences in established covalent EGFR TKIs and the assays used to accurately judge their potency and selectivity for EGFR variants including WT and the activating mutations responsible for drug resistance.…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

“…Molecules of this type are not mutant selective, and exhibit high WT potency, but share structural elements with C797S mutantselective inhibitors. 28 The molecules featured in Scheme 1 and Figure 1 are well-studied and are examples of the diverse binding modes for covalent EGFR TKIs, which are informative for understanding the methods utilized to determine and interpret their potency and mutant-selectivity. 21,28…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

“…28 The molecules featured in Scheme 1 and Figure 1 are well-studied and are examples of the diverse binding modes for covalent EGFR TKIs, which are informative for understanding the methods utilized to determine and interpret their potency and mutant-selectivity. 21,28…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Pitfalls and considerations in determining the potency and mutant selectivity of covalent epidermal growth factor receptor inhibitors

Hoyt,

Urul,

Ogboo

et al. 2023

Preprint

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Pursuing enzyme inhibitors with molecules that form covalent bonds with the desired target is an attractive focus in drug development that is increasing in prevalence. However, challenges arise when carrying out assessments of their time-dependent inhibitory properties as well as making correlations with values reported in the literature. Given the prominent focus on the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase in oncology, and the diverse structures and binding modes of covalent EGFR inhibitors, this perspective seeks to explore various broadly relevant factors that arise in the measurement of kinetic parameters within this class of drugs. A review of several studies indicates that variable literature potency values require investigators to include appropriate reference molecules and consistent substrate conditions for experimental consistency and proper benchmarks. The impact on covalent inhibitor potency with respect to common buffer conditions and compound liquid handling is surveyed highlighting the importance of multiple experimental variables when conducting these assays. Additionally, when assessing the potency for inhibitor selectivity in targeting EGFR mutants over wild-type (WT), it is ideal to consider ratios of true potency due to the variable ATP substrate binding affinities. The overview presented here, although most directly applicable to the tyrosine kinase inhibitor field, serves inhibitor assessments broadly by providing guided insights into conducting biochemical assays for designing and validating next-generation covalent inhibitors.

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Section: Egfr Inhibitorsmentioning

confidence: 99%

Section: Egfr Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Pitfalls and considerations in determining the potency and mutant selectivity of covalent epidermal growth factor receptor inhibitors

Hoyt,

Urul,

Ogboo

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

L858R/L718Q and L858R/L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen Bonds

Imam,

Al Adawi,

Liu

et al. 2024

Proteins

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Acquired resistance to first‐line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all‐atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild‐type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue‐residue and residue‐solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.

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Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent “Type V” Kinase Inhibitors

Wittlinger,

Chitnis,

Pham

et al. 2024

J. Med. Chem.

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Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored. This study investigates the structure−activity relationships, binding modes, and biological activity of ATP-allosteric bivalent inhibitors (AABIs). We find that AABIs selectively inhibit drug-resistant EGFR mutants (L858R/T790M and L858R/T790M/C797S) by anchoring a methyl isoindolinone moiety along the αC-helix channel of the allosteric site. In contrast, related Type I 1 / 2 inhibitors target wild-type EGFR but are less effective against resistant mutants. This shift in selectivity demonstrates that mutant-selective AABIs classify as "Type V" bivalent inhibitors.

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Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors

Cited by 3 publications

References 63 publications

Pitfalls and considerations in determining the potency and mutant selectivity of covalent epidermal growth factor receptor inhibitors

Pitfalls and considerations in determining the potency and mutant selectivity of covalent epidermal growth factor receptor inhibitors

L858R/L718Q and L858R/L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen Bonds

Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent “Type V” Kinase Inhibitors

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