Selected Approaches to Disrupting Protein-Protein Interactions Within the MAPK/RAS Pathway

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Apr 28

PMID 37108538

Authors

Stephen J Harwood

Christopher R Smith

J David Lawson

John M Ketcham

Affiliations

Soon will be listed here.

Abstract

Within the MAPK/RAS pathway, there exists a plethora of protein-protein interactions (PPIs). For many years, scientists have focused efforts on drugging KRAS and its effectors in hopes to provide much needed therapies for patients with -mutant driven cancers. In this review, we focus on recent strategies to inhibit RAS-signaling via disrupting PPIs associated with SOS1, RAF, PDEδ, Grb2, and RAS.

Citing Articles

Insights into direct KRAS inhibition strategies for cancer treatment.

Li T, Gu C, Zhou C, Mao C, Yang K, Xu J Future Med Chem. 2024; 16(22):2411-2429.

PMID: 39569642 PMC: 11622815. DOI: 10.1080/17568919.2024.2424149.

The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading.

Sudhakar N, Yan L, Qiryaqos F, Engstrom L, Laguer J, Calinisan A Mol Cancer Ther. 2024; 23(10):1418-1430.

PMID: 38904222 PMC: 11443210. DOI: 10.1158/1535-7163.MCT-23-0870.

RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives.

Alawieh D, Cysique-Foinlan L, Willekens C, Renneville A Blood Cancer J. 2024; 14(1):72.

PMID: 38658558 PMC: 11043080. DOI: 10.1038/s41408-024-01054-2.

The permissive binding theory of cancer.

Weisman C Front Oncol. 2023; 13:1272981.

PMID: 38023252 PMC: 10666763. DOI: 10.3389/fonc.2023.1272981.

References

Sosman J, Kim K, Schuchter L, Gonzalez R, Pavlick A, Weber J . Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366(8):707-14. PMC: 3724515. DOI: 10.1056/NEJMoa1112302. View

Henry J, Kaufman M, Peng S, Mi Ahn Y, Caldwell T, Vogeti L . Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells. J Med Chem. 2015; 58(10):4165-79. DOI: 10.1021/acs.jmedchem.5b00067. View

Ostrem J, Peters U, Sos M, Wells J, Shokat K . K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013; 503(7477):548-51. PMC: 4274051. DOI: 10.1038/nature12796. View

Liang J, Edelsbrunner H, Woodward C . Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design. Protein Sci. 1998; 7(9):1884-97. PMC: 2144175. DOI: 10.1002/pro.5560070905. View

Zhou C, Fan Z, Zhou Z, Li Y, Cui R, Liu C . Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations. J Med Chem. 2022; 65(5):3923-3942. DOI: 10.1021/acs.jmedchem.1c01774. View

Fell J, Fischer J, Baer B, Blake J, Bouhana K, Briere D . Identification of the Clinical Development Candidate , a Covalent KRAS Inhibitor for the Treatment of Cancer. J Med Chem. 2020; 63(13):6679-6693. DOI: 10.1021/acs.jmedchem.9b02052. View

Ramharter J, Kessler D, Ettmayer P, Hofmann M, Gerstberger T, Gmachl M . One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS. J Med Chem. 2021; 64(10):6569-6580. DOI: 10.1021/acs.jmedchem.0c01949. View

Valkov E, Sharpe T, Marsh M, Greive S, Hyvonen M . Targeting protein-protein interactions and fragment-based drug discovery. Top Curr Chem. 2011; 317:145-79. DOI: 10.1007/128_2011_265. View

Twarog N, Low J, Currier D, Miller G, Chen T, Shelat A . Robust Classification of Small-Molecule Mechanism of Action Using a Minimalist High-Content Microscopy Screen and Multidimensional Phenotypic Trajectory Analysis. PLoS One. 2016; 11(2):e0149439. PMC: 4757101. DOI: 10.1371/journal.pone.0149439. View

10.

Yelland T, Garcia E, Parry C, Kowalczyk D, Wojnowska M, Gohlke A . Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling. J Med Chem. 2022; 65(3):1898-1914. PMC: 8842248. DOI: 10.1021/acs.jmedchem.1c01265. View

11.

Wells J, McClendon C . Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature. 2007; 450(7172):1001-9. DOI: 10.1038/nature06526. View

12.

Li L, Wu Y, Yang Z, Xu C, Zhao H, Liu J . Discovery of KRas G12C-IN-3 and Pomalidomide-based PROTACs as degraders of endogenous KRAS G12C with potent anticancer activity. Bioorg Chem. 2021; 117:105447. DOI: 10.1016/j.bioorg.2021.105447. View

13.

Leung E, Luo L, Liu Z, Wong V, Lu L, Xie Y . Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity. Cell Death Dis. 2018; 9(2):216. PMC: 5833846. DOI: 10.1038/s41419-017-0065-9. View

14.

Robert C, Grob J, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E . Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019; 381(7):626-636. DOI: 10.1056/NEJMoa1904059. View

15.

Lu H, Zhou Q, He J, Jiang Z, Peng C, Tong R . Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials. Signal Transduct Target Ther. 2020; 5(1):213. PMC: 7511340. DOI: 10.1038/s41392-020-00315-3. View

16.

Bekes M, Langley D, Crews C . PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov. 2022; 21(3):181-200. PMC: 8765495. DOI: 10.1038/s41573-021-00371-6. View

17.

Lipinski C . Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2014; 1(4):337-41. DOI: 10.1016/j.ddtec.2004.11.007. View

18.

Quevedo C, Cruz-Migoni A, Bery N, Miller A, Tanaka T, Petch D . Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat Commun. 2018; 9(1):3169. PMC: 6085350. DOI: 10.1038/s41467-018-05707-2. View

19.

Jiang Y, Zhuang C, Chen L, Lu J, Dong G, Miao Z . Structural Biology-Inspired Discovery of Novel KRAS-PDEδ Inhibitors. J Med Chem. 2017; 60(22):9400-9406. DOI: 10.1021/acs.jmedchem.7b01243. View

20.

Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T . Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021; 39(4):273-284. PMC: 8078423. DOI: 10.1200/JCO.20.02088. View