A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy

Bioorganic Chemistry, Journal Year: 2020, Volume and Issue: 99, P. 103811 - 103811

Published: April 2, 2020

Language: Английский

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Advances in covalent kinase inhibitors

Chemical Society Reviews, Journal Year: 2020, Volume and Issue: 49(9), P. 2617 - 2687

Published: Jan. 1, 2020

Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords unique set of advantages as well challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, irreversibly modify proximal nucleophilic residue on via reaction with an electrophile. To date, acrylamide group remains predominantly employed electrophile CKI development, its incorporation majority clinical candidates FDA approved therapies. Nonetheless, recent years considerable efforts ensued characterize alternative electrophiles that exhibit irreversible or reversibly binding mechanisms towards cysteine thiols other amino acids. This review article provides comprehensive overview CKIs reported literature over decade period, 2007-2018. Emphasis is placed rationale behind warhead choice, optimization approach, inhibitor design. Current are also highlighted, addition detailed analysis common trends themes observed within listed data set.

Language: Английский

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Covalent Inhibition in Drug Discovery

ChemMedChem, Journal Year: 2019, Volume and Issue: 14(9), P. 889 - 906

Published: Feb. 28, 2019

Although covalent inhibitors have been used as therapeutics for more than a century, there has general resistance in the pharmaceutical industry against their further development due to safety concerns. This inclination recently reverted after of wide variety address human health conditions along with US Food and Drug Administration (FDA) approval several use humans. Along this exciting resurrection an old drug discovery concept, review surveys enzymes that can be targeted by treatment diseases. We focus on protein kinases, RAS proteins, few other studied extensively targets inhibition, aim challenges designing effective drugs provide suggestions area yet explored.

Language: Английский

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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

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Discovery of Potent and Selective Epidermal Growth Factor Receptor (EGFR) Bifunctional Small-Molecule Degraders

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(3), P. 1216 - 1232

Published: Jan. 2, 2020

Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed and approved by Food Drug Administration for the treatment of non-small-cell lung cancers, but their efficacy can be compromised acquired drug resistance conferred EGFR-mutant variants. Here, we described discovery a novel E3 ligase von Hippel–Lindau-recruiting EGFR degrader, MS39 (compound 6), first-in-class cereblon-recruiting MS154 10), using proteolysis targeting chimera technology. These compounds potently induced degradation mutant not wild-type in an ligase-dependent manner cancer cell lines effectively suppressed cells compared with corresponding negative controls. The global proteomic analyses revealed that were highly selective EGFR. Furthermore, both bioavailable mouse pharmacokinetic studies, compound 6 is first degrader suitable vivo studies. Overall, provide set well-characterized chemical tools to research community.

Language: Английский

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Targeting EGFR^L858R/T790M and EGFR^{L858R/T790M/C797S} resistance mutations in NSCLC: Current developments in medicinal chemistry

Medicinal Research Reviews, Journal Year: 2018, Volume and Issue: 38(5), P. 1550 - 1581

Published: Jan. 26, 2018

Both the first-generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib second-generation covalent tyrosine kinase inhibitor (EGFR-TKI) afatinib have significantly improved survival of non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFRT790M mutation leads to clinically acquired resistance first- EGFR-TKIs drugs. A number third-generation wild-type sparing inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, PF0674775, been developed, among which AZD9291 has approved by US FDA treatment NSCLC . More recently, tertiary EGFRC797S was reported as dominant mechanism irreversible inhibitors. It is highly desirable develop fourth-generation This review summarizes mechanisms latest medicinal chemistry advances on third- special attention being paid allosteric combating mutation.

Language: Английский

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Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer

Journal of Medicinal Chemistry, Journal Year: 2017, Volume and Issue: 61(10), P. 4290 - 4300

Published: Nov. 14, 2017

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development treatment of non-small-cell lung cancer (NSCLC). current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically patients with NSCLC. However, high percentage these treated developed tertiary cystein-797 to serine-790 (C797S) mutation in kinase domain. This C797S is thought induce resistance all irreversible TKIs. In this Miniperspective, we present key mechanisms response TKIs, and emerging reports on novel TKIs combat resistance. Specifically, analyze allosteric ATP-competitive inhibitors terms discovery, binding mechanism, their potency selectivity against harboring mutations. Lastly, provide some perspectives new challenges future directions field.

Language: Английский

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Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors

Drug Discovery Today, Journal Year: 2017, Volume and Issue: 23(3), P. 745 - 753

Published: Oct. 12, 2017

Language: Английский

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Tyrosine kinase inhibitors enhanced the efficacy of conventional chemotherapeutic agent in multidrug resistant cancer cells

Molecular Cancer, Journal Year: 2018, Volume and Issue: 17(1)

Published: Feb. 15, 2018

Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporter such as ABCB1, ABCC1, ABCG2 limited successful cancer chemotherapy. Unfortunately, no commercial available MDR modulator approved FDA was used in clinic. Tyrosine kinase inhibitors (TKIs) have been administrated to fight against for decades. Almost TKI alone However, drug combinations acting synergistically kill cells become increasingly important chemotherapy an approach the recurrent resistant disease. Here, we summarize effect of TKIs on enhancing efficacy conventional chemotherapeutic ABC transporter-mediated cells, which encourage further discuss and study

Language: Английский

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Targeting EGFR in Lung Cancer: Current Standards and Developments

Drugs, Journal Year: 2018, Volume and Issue: 78(9), P. 893 - 911

Published: June 1, 2018

Language: Английский

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