Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands

Niggenaber, Janina; Heyden, Leonie; Grabe, Tobias; Müller, Matthias; Lategahn, Jonas; Rauh, Daniel

doi:10.1021/acsmedchemlett.0c00472

Cited by 33 publications

(30 citation statements)

References 29 publications

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“…Also, most recently growing interest in the development of hybrid compounds for ErbBfamily can be observed in literature. [22][23][24] Examples of the combination of conventional amino quinazoline scaffold plus EAI045-like motifs with reversible binding modus for EGFR showed similar behaviour to our study. While high potency for L858R/T790M/C797S mutation is achieved, they lack efficient selectivity against wt enzyme.…”

Section: Discussionsupporting

confidence: 86%

Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

Wittlinger¹,

Heppner²,

To³

et al. 2020

Preprint

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Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants

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Section: Discussionsupporting

confidence: 86%

Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

Wittlinger¹,

Heppner²,

To³

et al. 2020

Preprint

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“…To circumvent acquired drug-resistance against TKIs, a set of allosteric inhibitors targeting EGFR were previously introduced, including EAI001, EAI045, and JBJ-04-125-02 (shortened as “JBJ” in the article) ( Figure 1 E) [ 20 , 42 , 43 , 44 ]. To our knowledge, all current allosteric EGFR inhibitors target the MEK-pocket, which is generated by the outward displacement of the αC-helix and was first identified in mitogen-activated protein (MAP) kinase kinases (MEKs) ( Figure 1 E) [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

et al. 2021

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Dual-targeting therapeutics by coadministration of allosteric and orthosteric drugs is drawing increased attention as a revolutionary strategy for overcoming the drug-resistance problems. It was further observed that the occupation of orthosteric sites by therapeutics agents has the potential to enhance allosteric ligand binding, which leads to improved potency of allosteric drugs. Epidermal growth factor receptor (EGFR), as one of the most critical anti-cancer targets belonging to the receptor tyrosine kinase family, represents a quintessential example. It was revealed that osimertinib, an ATP-competitive covalent EGFR inhibitor, remarkably enhanced the affinity of a recently developed allosteric inhibitor JBJ-04-125-02 for EGFRL858R/T790M. Here, we utilized extensive large-scale molecular dynamics simulations and the reversed allosteric communication to untangle the detailed molecular underpinning, in which occupation of osimertinib at the orthosteric site altered the overall conformational ensemble of EGFR mutant and reshaped the allosteric site via long-distance signaling. A unique intermediate state resembling the active conformation was identified, which was further stabilized by osimertinib loading. Based on the allosteric communication pathway, we predicted a novel allosteric site positioned around K867, E868, H893, and K960 within the intermediate state. Its correlation with the orthosteric site was validated by both structural and energetic analysis, and its low sequence conservation indicated the potential for selective targeting across the human kinome. Together, these findings not only provided a mechanistic basis for future clinical application of the dual-targeting therapeutics, but also explored an innovative perception of allosteric inhibition of tyrosine kinase signaling.

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“…In preclinical studies, this combination treatment has been shown to render EGFR mutant NSCLC cells unable to acquire resistance, likely due to the orthogonal mechanisms of resistance to osimertinib versus the allosteric inhibitor. 60 A second compound class with a dibenzodiazepinone core was discovered in the same screen that led to EAI045. 38 A co-crystal structure with a representative dibenzodiazepinone, DDC4002, demonstrated that these compounds bind the same pocket as EAI045 and its derivatives, with related ligandprotein interactions despite their very different chemical structures (Figure 2I).…”

Section: Egfr-first-generation To Third-generation Inhibitors and Beyondmentioning

confidence: 99%

“…Thus, a unique avenue for treatment may involve combination therapy with a structurally compatible third‐generation TKI such as osimertinib. In preclinical studies, this combination treatment has been shown to render EGFR mutant NSCLC cells unable to acquire resistance, likely due to the orthogonal mechanisms of resistance to osimertinib versus the allosteric inhibitor 60 . A second compound class with a dibenzodiazepinone core was discovered in the same screen that led to EAI045 38 .…”

Section: Egfr—first‐generation To Third‐generation Inhibitors and Beyondmentioning

confidence: 99%

A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer

Heppner

Eck

2021

Protein Science

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Precision oncology is premised on identifying and drugging proteins and pathways that drive tumorigenesis or are required for survival of tumor cells. Across diverse cancer types, the signaling pathway emanating from receptor tyrosine kinases on the cell surface to RAS and the MAP kinase pathway is the most frequent target of oncogenic mutations, and key proteins in this signaling axis including EGFR, SHP2, RAS, BRAF, and MEK have long been a focus in cancer drug discovery. In this review, we provide an overview of historical and recent efforts to develop inhibitors targeting these nodes with an emphasis on the role that an understanding of protein structure and regulation has played in inhibitor discovery and characterization. Beyond its well-established role in structure-based drug design, structural biology has revealed mechanisms of allosteric regulation, distinct effects of activating oncogenic mutations, and other vulnerabilities that have opened new avenues in precision cancer drug discovery.

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Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands

Cited by 33 publications

References 29 publications

Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication

A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer

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