Design of Orally-bioavailable Tetra-cyclic phthalazine SOS1 inhibitors with high selectivity against EGFR.

Humans SOS1 Protein / genetics Proto-Oncogene Proteins p21(ras) / genetics Mutation Quinazolines / pharmacology ErbB Receptors / genetics
EGFR KRAS Protein–protein interaction SOS1 Tetra-cyclic phthalazine

Journal

Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703

Informations de publication

Date de publication:
07 2023
Historique:
received: 16 01 2023
revised: 28 02 2023
accepted: 07 04 2023
medline: 29 5 2023
pubmed: 14 4 2023
entrez: 13 4 2023
Statut: ppublish

Résumé

KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many deadliest cancers. Son of sevenless homolog 1 (SOS1) is a crucial regulator of KRAS to modulate KRAS from inactive to active states. We previously discovered tetra-cyclic quinazolines as an improved scaffold for inhibiting SOS1-KRAS interaction. In this work, we report the design of tetra-cyclic phthalazine derivatives for selectively inhibiting SOS1 against EGFR. The lead compound 6c displayed remarkable activity to inhibit the proliferation of KRAS(G12C)-mutant pancreas cells. 6c showed a favorable pharmacokinetic profile in vivo, with a bioavailability of 65.8% and exhibited potent tumor suppression in pancreas tumor xenograft models. These intriguing results suggested that 6c has the potential to be developed as a drug candidate for KRAS-driven tumors.

Identifiants

DOI: 10.1016/j.bioorg.2023.106536 PMID: 37054529
pubmed: 37054529
pii: S0045-2068(23)00196-7
doi: 10.1016/j.bioorg.2023.106536
pii:
doi:

Substances chimiques

SOS1 Protein 0
Proto-Oncogene Proteins p21(ras) EC 3.6.5.2
Quinazolines 0
ErbB Receptors EC 2.7.10.1
EGFR protein, human EC 2.7.10.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

106536

Informations de copyright

Copyright © 2023 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [S.L.Z., H.H. are or were Wuhan Yuxiang Pharmaceutial Technology Co., Ltd. employees or consultants at the time that the work was conducted. H. X. F. is shareholder of Wuhan Yuxiang Pharmaceutial Technology Co., Ltd.].

Auteurs

Huan He (H)

School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China; Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan 430200, PR China.

Ruiqi Chen (R)

Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China.

Ziwei Wang (Z)

Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China.

Luolong Qing (L)

Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China.

Yu Zhang (Y)

Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China.

Yi Liu (Y)

Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China; School of Chemical and Environmental Engineering, Wuhan Polytechnic University, Wuhan 430023, PR China; Hubei Key Laboratory of Radiation Chemistry and Functional Materials, Hubei University of Science and Technology, Xianning 437100, PR China.

Weidong Pan (W)

School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China. Electronic address: wdpan@163.com.

Huaxiang Fang (H)

Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China. Electronic address: fang_huaxiang@whyxpharma.com.

Silong Zhang (S)

School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, PR China; Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan 430200, PR China. Electronic address: silongzhang@whu.edu.cn.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Design of Orally-bioavailable Tetra-cyclic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Facteurs d'échange de nucléotides guanyliques › Facteur ras d'échange de nucléotides guanyliques › Protéines Son of sevenless › Protéine SOS1 › Design of Orally-bioavailable Tetra-cyclic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes p21(ras) › Design of Orally-bioavailable Tetra-cyclic...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Design of Orally-bioavailable Tetra-cyclic...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinazolines › Design of Orally-bioavailable Tetra-cyclic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs ErbB › Design of Orally-bioavailable Tetra-cyclic...