Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

Engel, Julian; Richters, André; Getlik, Matthäus; Tomassi, Stefano; Keul, Marina; Termathe, Martin; Lategahn, Jonas; Becker, Christian; Mayer‐Wrangowski, Svenja; Grütter, Christian; Uhlenbrock, Niklas; Krüll, Jasmin; Schaumann, Niklas; Eppmann, Simone; Kibies, Patrick; Hoffgaard, Franziska; Heil, Jochen; Menninger, Sascha; Ortiz-Cuarán, Sandra; Heuckmann, Johannes M.; Tinnefeld, Verena; Zahedi, René P.; Sos, Martin L.; Schultz‐Fademrecht, Carsten; Thomas, Roman K.; Kast, Stefan M.; Rauh, Daniel

doi:10.1021/acs.jmedchem.5b01082

Cited by 93 publications

(83 citation statements)

References 86 publications

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“…Starting from hit compound 1, which emerged from a phenotypic screen of 1500 compounds against 80 NSCLC cell lines, Engel et al. presented a structure‐guided development of several irreversible inhibitors that could selectively target the L858R/T790M mutant form of EGFR (Figure ) . Subsequent synthesis of a large number of analogues led to the discovery of indazole analogue 2 , which was characterized as the most active compound, with IC 50 values toward L858R/T790M, L858R, and wild‐type EGFR of 0.07, 0.50 and 1.70 μ m , respectively.…”

Section: Indazole Derivatives As Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Recent Advances in the Development of Indazole‐based Anticancer Agents

et al. 2018

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Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole-containing derivatives are endowed with a broad range of biological properties, including anti-inflammatory, antimicrobial, anti-HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure-activity relationships of these compounds.

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Section: Indazole Derivatives As Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Recent Advances in the Development of Indazole‐based Anticancer Agents

et al. 2018

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“…One of these pyrimidines, Osimertinib [18] was approved by the FDA in November 2015, while and Rociletinib [19], was not approved for treatment of non-small-cell lung cancer [20–21]. The search for the next generation of covalent EGFR inhibitors continues, guided by rational design and lessons learned from the clinic [22]. …”

Section: Improving Drug Properties For Known Scaffoldsmentioning

confidence: 99%

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

Hallenbeck¹,

Turner²,

Renslo³

et al. 2016

CTMC

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The targeting of non-catalytic cysteine residues with small molecules is drawing increased attention from drug discovery scientists and chemical biologists. From a biological perspective, genomic and proteomic studies have revealed the presence of cysteine mutations in several oncogenic proteins, suggesting both a functional role for these residues and also a strategy for targeting them in an ‘allele specific’ manner. For the medicinal chemist, the structure-guided design of cysteine-reactive molecules is an appealing strategy to realize improved selectivity and pharmacodynamic properties in drug leads. Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation. Here, we review three applications of cysteine-modifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each case, structure-guided design plays a key role in determining which cysteine residue(s) to target and in designing compounds with the proper geometry to enable both covalent interaction with the targeted cysteine and productive non-covalent interactions with nearby protein residues.

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“…There is a meta-acrylamide that points to Cys797 and forms the covalent bond. This compound also has activities against other kinases, such as FAK, CHK2, ErBB4, and JAK3 [42, 43]. A metabolite of rociletinib, M502, has potency against insulin receptor and insulin-like growth factor 1 receptor, which may lead to the AE of hyperglycemia [44].…”

Section: Main Text Of the Reviewmentioning

confidence: 99%

Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors

et al. 2016

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The first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (1/2G EGFR-TKIs) gefitinib, erlotinib, and afatinib have all been approved as standard first-line treatments for advanced EGFR mutation-positive non-small cell lung cancer. The third-generation (3G) EGFR-TKIs have been developed to overcome the EGFR T790M mutation, which is the most common mechanism of acquired resistance to 1/2G EGFR-TKI treatment. This resistance mutation develops in half of the patients who respond to 1/2G EGFR-TKI therapy. The structures of the novel 3G EGFR-TKIs are different from those of 1/2G EGFR-TKIs. Particularly, 3G EGFR-TKIs have lower affinity to wild-type EGFR, and are therefore associated with lower rates of skin and gastrointestinal toxicities. However, many of the adverse events (AEs) that are observed in patients receiving 3G EGFR-TKIs have not been observed in patients receiving 1/2G EGFR-TKIs. Although preclinical studies have revealed many possible mechanisms for these AEs, the causes of some AEs remain unknown. Many mechanisms of resistance to 3G EGFR-TKI therapy have also been reported. Here, we have reviewed the recent clinical and preclinical developments related to novel 3G EGFR-TKIs, including osimertinib, rociletinib, olmutinib, EGF816, and ASP8273.

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Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

Cited by 93 publications

References 86 publications

Recent Advances in the Development of Indazole‐based Anticancer Agents

Recent Advances in the Development of Indazole‐based Anticancer Agents

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

Update on recent preclinical and clinical studies of T790M mutant-specific irreversible epidermal growth factor receptor tyrosine kinase inhibitors

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