Multivalent Small-Molecule Pan-RAS Inhibitors

被引：213

作者：

Welsch, Matthew E. ^{[1
]}

Kaplan, Anna ^{[2
]}

Chambers, Jennifer M. ^{[2
]}

Stokes, Michael E. ^{[2
,4
]}

Bos, Pieter H. ^{[2
]}

Zask, Arie ^{[2
]}

Zhang, Yan ^{[1
]}

Sanchez-Martin, Marta ^{[3
]}

Badgley, Michael A. ^{[5
]}

Huang, Christine S. ^{[2
]}

Tran, Timothy H. ^{[2
]}

Akkiraju, Hemanth ^{[2
,6
]}

Brown, Lewis M. ^{[2
,6
]}

Nandakumar, Renu ^{[7
]}

Cremers, Serge ^{[4
,7
]}

Yang, Wan Seok ^{[8
]}

Tong, Liang ^{[2
]}

Olive, Kenneth P. ^{[4
,5
]}

Ferrando, Adolfo ^{[3
,4
,9
]}

Stockwell, Brent R. ^{[1
,2
]}

机构：

[1] Columbia Univ, Dept Chem, New York, NY 10027 USA

[2] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[3] Columbia Univ, Med Ctr, Inst Canc Genet, New York, NY 10032 USA

[4] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA

[5] Columbia Univ, Dept Med, Med Ctr, Div Digest & Liver Dis, New York, NY 10032 USA

[6] Columbia Univ, Quantitat Prote & Metabol Ctr, New York, NY 10027 USA

[7] Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, New York, NY 10032 USA

[8] St Johns Univ, Dept Biol Sci, Queens, NY 11439 USA

[9] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA

来源：

CELL | 2017年 / 168卷 / 05期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

MEDIATED NUCLEOTIDE EXCHANGE; PROTEIN-PROTEIN INTERACTIONS; K-RAS; STRUCTURAL BASIS; CANCER-THERAPY; TARGETING RAS; CELLS; ACTIVATION; DISCOVERY; ONCOGENES;

D O I：

10.1016/j.cell.2017.02.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.

引用

页码：878 / +

页数：41

共 55 条

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