Strategies to overcome drug resistance using SHP2 inhibitors

Li, Meng; Gao, Shan; Elhassan, Reham M.; Hou, Xuben; Fang, Hao

doi:10.1016/j.apsb.2021.03.037

Cited by 24 publications

(14 citation statements)

References 130 publications

(219 reference statements)

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“…Allostery, as the second secret of life, governs a myriad of critical biological events and is thus gaining increasing interest in the pharmaceutical field. In recent years, more and more allosteric therapeutic agents are entering clinical tracks, conquering a wide range of notoriously intractable drug targets in history such as Ras GTPase, 32,158,199,[248][249][250][251][252] SHP2 kinase, [253][254][255][256][257][258] and GPCRs. 26,71,72,[259][260][261][262][263][264] Promising allosteric therapeutics include K-Ras G12C inhibitor Sotorasib, BCR-ABL inhibitor Asciminib and CCR5 antagonist Maraviroc, and so on.…”

Section: Discussionmentioning

confidence: 99%

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Chai

Wang

et al. 2021

WIREs Comput Mol Sci

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Allostery is a universal, biological phenomenon in which orthosteric sites are finetuned by topologically distal allosteric sites triggered by perturbations, such as ligand binding, residue mutations, or post-translational modifications. Allosteric regulation is implicated in a variety of physiological and pathological conditions and is thus emerging as a novel avenue for drug discovery. Allosteric drugs have traditionally been discovered by serendipity through large-scale experimental screening. Recently, we have witnessed significant progress in biophysics, particularly in structural bioinformatics, which has facilitated the in-depth characterization of allosteric effects and the accurate detection of allosteric residues and exosites. These advances improve our understanding of allosterism and promote allosteric drug discovery, thereby revolutionizing the shift from the traditional serendipitous route used to discover allosteric drugs to the updated path centered on rational structure-based design. In this review, recent advances in computational methods applied to allosteric drug discovery are summarized. We comprehensively review these achievements along various levels of allosteric events, from the construction of allosteric databases to the identification and analysis of allosteric residues, signals, sites, and modulators. We expect to increase the awareness of the discovery of allosteric drugs using structure-based computational methods.

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Section: Discussionmentioning

confidence: 99%

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Chai

Wang

et al. 2021

WIREs Comput Mol Sci

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“…Recent studies have uncovered the effect of SHP2 on T-cell exhaustion in a tumor microenvironment [ 95 , 96 ]. After binding to PD-L1, PD-1 recruits SHP2 via the phosphorylation of its tyrosine-containing motifs, subsequently inducing a cascade of downstream pathways for T-cell suppression, such as abrogation of the T-cell receptor (TCR) and CD28, deprivation of cytokine production and impairment of T-cell proliferation [ 91 , 93 , 95 , 97 ]. Hence, targeting SHP2 might significantly potentiate PD-1/PD-L1 blockade therapy.…”

Section: Small-molecule Protacs Targeting Pd-1/pd-l1 Checkpoint Signa...mentioning

confidence: 99%

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

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Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a Cancer Patients. Bosn. J. Basic novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

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“…Allosteric inhibitors designed based on the unique allosteric regulation of SHP2 have showed advantages in overcoming the selectivity and bioavailability issues of orthosteric SHP2 inhibitors 52,53 . Sitemap analysis predicted three different types of allosteric binding pockets at the multidomain interfaces between SH2 and PTP domains: (1) the “tunnel” allosteric site 1 at the C‐SH2/PTP domain interface; (2) the “latch” allosteric site 2 at the N‐SH2/PTP domain interface that located approximately 20 Å away from the tunnel; (3) the “groove” allosteric site 3 at the N‐SH2/PTP domain interface that resided on the opposite side of the tunnel site 54 .…”

Section: Molecular Basis Of Shp2 Inhibitorsmentioning

confidence: 99%

Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

Song

Yang

Wang

et al. 2022

Medicinal Research Reviews

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The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy. The dynamic change of SHP2 between closed and open conformations under either physiological or pathological conditions provides opportunities to design SHP2 inhibitors for treating SHP2-related diseases. To date, several SHP2 allosteric inhibitors have advanced into clinical trials as mono-or combined therapy of cancers. In this review, we provide an overview on the structural landscape of SHP2 under physiological and pathological conditions and also comprehensively analyze the binding models of SHP2/inhibitor complexes. Structural features of SHP2 under pathological conditions and co-crystal structures of SHP2/inhibitor complexes will definitely facilitate structure-guided design of SHP2 inhibitors. Finally, proteolysis targeting chimeric (PROTAC) based SHP2 degraders have shown therapeutic promise for cancer therapy and are also briefly discussed. We hope this review could provide

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Strategies to overcome drug resistance using SHP2 inhibitors

Cited by 24 publications

References 130 publications

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

Small-Molecule PROTACs for Cancer Immunotherapy

Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

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