Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non–small cell lung cancer

Huang, Wei‐Sheng; Li, Feng; Gong, Yongjin; Zhang, Yun; Youngsaye, Willmen; Xu, Yan; Zhu, Xiaotian; Greenfield, Matthew T.; Kohlmann, Anna; Taslimi, Paul; Toms, A.V.; Zech, Stephan G.; Zhou, Tianjun; Das, Biplab; Jang, Hyun Gyung; Tugnait, Meera; Ye, Yihua E.; Gonzalvez, François; Baker, Theresa E.; Nadworny, Sara; Ning, Yaoyu; Wardwell, Scott; Zhang, Sen; Gould, Alexandra E.; Hu, Yongbo; Lane, Weston; Skene, R.J.; Zou, Hua; Clackson, Tim; Narasimhan, Narayana I.; Rivera, Victor M.; Shakespeare, William C.

doi:10.1016/j.bmcl.2022.129084

Cited by 8 publications

(7 citation statements)

References 24 publications

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“…25 This revealed that 13 had relatively low reactivity (t 1/2 = 2960 min) when compared to known covalent drugs such as 3 (t 1/2 = 121 min) 6 and thus further analogues were synthesized with an increased reactivity relative to 13 to try to improve potency. Both the alkyne amide (14) and sulfonamide (15) were synthesized and tested and both compounds increased potency along with increasing reactivity (t 1/2 = 55 and 69 min respectively). This indicates that we are forming a covalent interaction with Cys797 using this vector and as expected an increase in reactivity is leading to an increase in potency.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Fractions containing the desired product were evaporated to dryness to afford 6,7-dimethoxy-4-(3-(3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2yl)-1H-pyrazol-4-yl)quinazoline (2.14 g, 92%) as a pale-yellow foam. (14). A solution of propiolic acid (0.013 mL, 0.21 mmol) in DCM (50 μL) was added dropwise to a stirred solution of 2-(4-(6,7-dimethoxyquinazolin-4-yl)-3-(3-methoxyphenyl)-1H-pyrazol-1-yl)ethan-1amine (78 mg, 0.19 mmol), N-ethyl-N-isopropylpropan-2-amine (0.050 mL, 0.29 mmol) and HATU (88 mg, 0.23 mmol) in DCM (1.5 mL) at −50 °C.…”

Section: 7-dimethoxy-4-(3-(3-methoxyphenyl)-1-(tetrahydro-2hpyran-2-y...mentioning

confidence: 99%

“…However, the recent approval of amivantamab, a bispecific antibody, marks a significant step forward for patients with Ex20Ins . In addition, mobocertinib ( 4 ), a small molecule therapy, was also approved for patients with Ex20Ins but has since been withdrawn by the FDA . Numerous other inhibitors, including CLN-081 ( 5 ), are currently undergoing clinical evaluation. , However, similar to improvements observed for osimertinib ( 3 ) in patients with Ex19 del and/or L858R activating mutations, there remains scope for development of improved Ex20Ins inhibitors with additional WT margin and blood brain barrier penetration, and thus the potential to improve efficacy and tolerability when compared to existing medicines and development candidates for patients with Ex20Ins.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

Thomson,

Barton,

Braybrooke

et al. 2024

J. Med. Chem.

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Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: 7-dimethoxy-4-(3-(3-methoxyphenyl)-1-(tetrahydro-2hpyran-2-y...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

Thomson,

Barton,

Braybrooke

et al. 2024

J. Med. Chem.

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“…However, the murine pharmacokinetic parameters for the tricyclic compounds following 10 mg/kg oral dosing were not improved compared to osimertinib. In further optimization the tricycle was removed and a subsequent isopropyl ester substituted compound, named mobocertinib, demonstrated a substantial improvement in murine plasma exposure following oral administration and was advanced to clinical development . A co-crystal structure of mobocertinib in complex with EGFR D770_N771insNPG/V984R explained the potency improvement induced by the isopropyl ester group.…”

Section: Egfr Ex20ins Inhibitorsmentioning

confidence: 96%

Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations

Chen,

Hu,

Patterson

et al. 2023

J. Med. Chem.

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Epidermal growth factor receptor (EGFR) targeted therapy is one of the most important and effective strategies to combat EGFR mutant nonsmall-cell lung cancer (NSCLC). However, a substantial number of patients bearing EGFR exon 20 insertion (Ex20ins) mutations respond poorly to common EGFR targeted therapies. This clinical need remained unmet until recently, when the EGFR Ex20ins mutation inhibitor mobocertinib was approved by the FDA. Despite this progress, the structural mechanisms of EGFR Ex20ins mutation resistance and characterization of inhibitor binding modes have not been systematically summarized. Herein, we analyze the structural mechanisms for ligand binding and resistance and summarize recent developments for the reported inhibitors of EGFR Ex20ins mutations. Furthermore, this Perspective aims to provide insights for the design of the next generation of EGFR Ex20ins inhibitors.

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“…To block oncogenic kinase activation, mobocertinib forms a covalent bond with EGFR -C797 and interacts with the gatekeeper residue through its isopropyl ester moiety which further selects for activity against EGFR exon 20 mutants ( 57 ). The drug is a derivate of osimertinib that was modified to achieve its properties in structural modeling and systems ( 127 , 128 ). As previously discussed, mobocertinib has demonstrated in vitro activity against models with EGFR or ERBB2 exon 20 insertion-mutated NSCLC ( 57 , 58 , 105 ).…”

Section: From Bench To Bedside: Use Of Egfr and ...mentioning

confidence: 99%

EGFR exon 20 insertion mutations and ERBB2 mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates

Sentana‐Lledo¹,

Academia²,

Viray³

et al. 2023

Transl Lung Cancer Res

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Background and Objective This review will provide an overview of EGFR and ERBB2 mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals. Methods We obtained data from the literature in accordance with narrative review reporting guidelines. Key Content and Findings EGFR mutations are present in up to 15–20% of all NSCLCs; amongst these, 10% correspond to kinase domain insertions in exon 20. Structurally similar, ERBB2 ( HER2 ) mutations occurs in 1–4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of EGFR exon 20 insertions occur within the loop following the regulatory C-helix and activate the kinase domain of EGFR without generating a therapeutic window to gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Mobocertinib represents a novel class of covalent EGFR inhibitors with a modest therapeutic window to these mutants and induces anti-tumor responses in a portion of patients [at 160 mg/day: response rate of <30% with duration of response (DoR) >17 months and progression-free survival (PFS) of >7 months] albeit with mucocutaneous and gastrointestinal toxicities. The bi-specific EGFR-MET antibody amivantamab-vmjw has modest but broad preclinical activity in EGFR-driven cancers and specifically for EGFR exon 20 insertion-mutated NSCLC has response rates <40% and PFS of <8.5 months at the cost of both infusion-related plus on-target toxicities. Both drugs were approved in 2021. The clinical development of kinase inhibitors for ERBB2 -mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib. However, the activation of ERBB2 has allowed for repurposing of antibody-drug conjugates (ADCs) that target ERBB2 with cytotoxic payloads. The FDA approved fam-trastuzumab deruxtecan-nxki in 2022 for NSCLC based on response rate of >55%, DoR >9 months, PFS >8 months and manageable adverse events (including cytopenias, nausea and less commonly pneumonitis). Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors. Conclusions The approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for EGFR exon 20 insertion-mutated and ERBB2 -mutated NSCLCs.

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Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non–small cell lung cancer

Cited by 8 publications

References 24 publications

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion (Ex20ins) Mutations

EGFR exon 20 insertion mutations and ERBB2 mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates

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