Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC

doi:10.1016/j.bmcl.2022.128718

Bioorganic & Medicinal Chemistry Letters

Volume 68, 15 July 2022, 128718

https://doi.org/10.1016/j.bmcl.2022.128718 Get rights and content

Abstract

The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg.

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Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.J.E. reports receiving a commercial research grant from Novartis Institutes for Biomedical Research, reports receiving other commercial research support from Takeda, and has been a consultant for Novartis Institutes for Biomedical Research. N.S.G. reports receiving a commercial research grant from Takeda and is a consultant or advisory board member for C4,

Acknowledgments

We thank Takeda Pharmaceuticals for funding support and scientific discussions. The rat PK study was conducted at WuXi AppTec. T.S.B is supported by a Ruth L. Kirschstein National Research Service Award (1F32CA247198-01). The crystallography work is based upon research conducted at the Northeastern Collaborative Access Team beamlines (P30 GM124165, P41 GM103403) utilizing resources of the Advanced Photon Source at the Argonne National Laboratory (DE-AC02-06CH11357).

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Cited by (10)

Discovery and current developments of isoindolinone-based fungal natural products
2023, European Journal of Medicinal Chemistry Reports
Most fungi generate secondary metabolites essential to their growth or used as chemical defense systems. They produce a large variety of small molecules, notably alkaloids containing an isoindolinone unit in the form of small bicyclic cichorine-type molecules more or less substituted, up to the form of extended, heavily substituted tri- or tetra-cyclic molecules equipped with one or two prenyl side chains. An extended family of more than 170 isoindolinone derivatives produced by mycelial or endophytic fungi has been identified and analyzed. These isoindolinone derivatives include many series such as the andicichorines, aspergillinines, caputmedusins, clitocybins, daldinans, emerimidines, emeriphenolicins, entonalactams, erinaceolactams, erinacerins, fendlerinines, marilines, meyeroguillines, stachartins, stachybotrins, stachybotrysams, sterenins, xylactams, and others compounds endowed with pharmacological properties described here. The family also includes isoindolinone dimers, notably potent fibrinolytic compounds, such as those designated Stachybotrys microspora triprenyl phenol (SMTP) with the lead product SMTP-7 (orniplabin) currently developed for the treatment of stroke. The repertoire of isoindolinone-based natural products produced by fungi is large (in contrast that of vascular plants) and comprises products with marked anti-inflammatory, antiviral, or anticancer activities. All these fungal isoindolinone-based products can be exploited for their medicinal properties and to guide the design of functionalized analogues targeting different enzymes or pathways. The chemical or biosynthetic access to these products is evoked and the most potent derivatives are underlined. Altogether, the review offers an exhaustive repertoire of isoindolinones of fungal origin and their pharmacological properties.
Recent advances of novel fourth generation EGFR inhibitors in overcoming C797S mutation of lung cancer therapy
2023, European Journal of Medicinal Chemistry
Citation Excerpt :
Therefore, in the future, pharmacists can use compound 26 as a lead compound to optimize its structure and improve cell activity. Gero et al. [42] explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. In the H1975 efficacy model, a daily oral dose of 25 mg/kg of compound 27 (Fig. 10) showed tumor regression.
Lung cancer is the second place among the global cancer population in term of the morbidity and mortality, while non-small cell lung cancer (NSCLC) accounts for the largest proportion of all lung cancer patient. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are commonly used in the treatment of NSCLC. Despite of the success in coping with EGFR kinase resistance lung cancer using the first three generations of EGFR-TK inhibitors (EGFR-TKIs), the new problem of resistance to Osimertinib occurred due to the newly developed EGFR^C797S mutation. In recent years, scientists have proposed several pharmacochemical strategies for the treatment of Osimertinib-resistant NSCLC patients. This paper intends to collect the references in this field since 2021 and to summarize the pharmacochemical processes and strategies in discovery of novel EGFR-TKIs for overcoming C797S mutation in lung cancer patients. It could serve as quick information provider for further structural modifications and drug discovery.
Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors
2023, Methods in Enzymology
Specificity for a desired enzyme target is an essential property of small-molecule inhibitors. Molecules targeting oncogenic driver mutations in the epidermal growth factor receptor (EGFR) kinase domain have had a considerable clinical impact due to their selective binding to cancer-causing mutants compared to wild type. Despite the availability of clinically approved drugs for cancers driven by EGFR mutants, persistent challenges in drug resistance in the past decades have led to newer generations of drugs with divergent chemical structures. The current clinical challenges are mainly due to acquired resistance to third-generation inhibitors, including by the acquisition of the C797S mutation. Several diverse fourth-generation candidates and tool compounds that inhibit the C797S mutant have emerged, and their structural characterization has revealed molecular factors that allow for EGFR mutant selective binding. Here, we have reviewed all known structurally-characterized EGFR TKIs targeting clinically-relevant mutations to identify specific features that enable C797S inhibition. Newer generation EGFR inhibitors exhibit consistent and previously underutilized hydrogen bonding interactions with the conserved K745 and D855 residue side chains. We also consider binding modes and hydrogen bonding interactions of inhibitors targeting the classical ATP and the more unique allosteric sites.
Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors
2022, European Journal of Medicinal Chemistry
Citation Excerpt :
To date, several allosteric kinase inhibitors that target the EGFR-C797S resistance mutation have been reported and EAI045 (Fig. 1) was the first one disclosed by Michael J. Eck. et al. [26–29]. Although EAI045 combined with anti-EGFR anti-body cetuximab was effective in genetically engineered EGFRL858R/T790M/C797S mice, further development was stopped due to its toxicity.
Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFR^{L858R/T790M/C797S} (IC₅₀ = 0.75 μM) and BaF3-EGFR^{19del/T790M/C797S} (IC₅₀ = 0.09 μM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR^{19del/T790M/C797S} cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR^{19del/T790M/C797S} xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.
A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology
2024, Molecular Pharmacology
Pitfalls and Considerations in Determining the Potency and Mutant Selectivity of Covalent Epidermal Growth Factor Receptor Inhibitors
2024, Journal of Medicinal Chemistry

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^g: Current Address: Department of Chemistry, University at Buffalo, Buffalo, NY 14260, USA.

^h: Current Address: Department of Medicinal Chemistry and Department of Chemistry and Systems Biology, Stanford University, Stanford, CA 94305, USA.

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Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC

Abstract

Graphical abstract

Section snippets

Declaration of Competing Interest

Acknowledgments

Pharmacol Res

Bioorg Chem

Lung Cancer

Bioorg Med Chem Lett

Small-molecule kinase inhibitors for the treatment of nononcologic diseases

J Med Chem

The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

Proc Natl Acad Sci U S A

Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR)

J Med Chem

Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor

J Med Chem