162012-67-1Relevant articles and documents
STEFs: Activated Vinylogous Protein-Reactive Electrophiles
Hansen, Bente K.,Loveridge, Christopher J.,Thyssen, Stine,W?rmer, Gustav J.,Nielsen, Andreas D.,Palmfeldt, Johan,Johannsen, Mogens,Poulsen, Thomas B.
, p. 3533 - 3537 (2019)
Reported here is the synthesis of a class of semi-oxamide vinylogous thioesters, designated STEFs, and the use of these agents as new electrophilic warheads. This work includes preparation of simple probes that contain this reactive motif as well as its installation on a more complex kinase inhibitor scaffold. A key aspect of STEFs is their reactivity towards both thiol and amine groups. Shown here is that amine conjugations in peptidic and proteinogenic samples can be facilitated by initial, fast conjugation to proximal thiol residues. Evidence that both the selectivity and the reactivity can be tuned by the structure of STEFs is provided, and given the unique ability of this functionality to conjugate by an addition-elimination mechanism, STEFs are electrophilic warheads that could find broad use in chemical biology.
Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase
Hur, Wooyoung,Velentza, Anastasia,Kim, Sungjoon,Flatauer, Laura,Jiang, Xinnong,Valente, David,Mason, Daniel E.,Suzuki, Melissa,Larson, Brad,Zhang, Jianming,Zagorska, Anna,DiDonato, Michael,Nagle, Advait,Warmuth, Markus,Balk, Steven P.,Peters, Eric C.,Gray, Nathanael S.
, p. 5916 - 5919 (2008)
Irreversible HER/erbB inhibitors selectively inhibit HER-family kinases by targeting a unique cysteine residue located within the ATP-binding pocket. Sequence alignment reveals that this rare cysteine is also present in ten other protein kinases including all five Tec-family members. We demonstrate that the Tec-family kinase Bmx is potently inhibited by irreversible modification at Cys496 by clinical stage EGFR inhibitors such as CI-1033. This cross-reactivity may have significant clinical implications.
Tyrosine kinase inhibitor and pharmaceutical application thereof
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, (2021/08/19)
The invention relates to a tyrosine kinase inhibitor containing a quinazoline derivative in the fields of tumor treatment medicines and the like, and application of the tyrosine kinase inhibitor in treatment medicines for inhibiting and treating diseases caused by overexpression of tyrosine kinase. The active ingredient of the tyrosine kinase inhibitor is a quinazoline derivative with a structure shown in the following formula: a functional group containing XCH2 (CH2) nC = O is introduced on the basis of a quinazoline structure, and the functional group is easily combined with cysteine sulfydryl through nucleophilic reaction to form a covalent bond so that the activity of tyrosine kinase is irreversibly inhibited.
Design, synthesis and evaluation of novel ErbB/HDAC multitargeted inhibitors with selectivity in EGFRT790M mutant cell lines
Zhao, Lei,Fan, Tingting,Shi, Zhichao,Ding, Chao,Zhang, Cunlong,Yuan, Zigao,Sun, Qinsheng,Tan, Chunyan,Chu, Bizhu,Jiang, Yuyang
, (2021/01/25)
Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI–H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI–H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI–H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI–H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
