Design and Synthesis of Tetrahydropyridothieno[2,3-<i>d</i>]pyrimidine Scaffold Based Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors: The Role of Side Chain Chirality and Michael Acceptor Group for Maximal Potency

Wu, Chia Hsien; Coumar, Mohane Selvaraj; Chu, Chang Ying; Lin, Wen Hsing; Chen, Yi Rong; Chen, Chiung Tong; Shiao, Hui Yi; Rafi, Shaik; Wang, Sing Yi; Hsu, Hui Wen; Chen, Chun Hwa; Chang, Chun Yu; Chang, Teng Yuan; Lien, Tzu-Wen; Fang, Ming-Yu; Yeh, Kai-Chia; Chen, Ching Ping; Yeh, Teng Kuang; Hsieh, Sheng-Hung; Hsu, Ju Wei; Liao, Chun‐Chen; Chao, Yu Sheng; Hsieh, Hsing Pang

doi:10.1021/jm100607r

Cited by 106 publications

(62 citation statements)

References 18 publications

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“…In 2010 Wu et al [19],altered a hitidentified from HTS through rational modification approach to obtain a series of novel and active tetrahydropyridothieno[2,3-d]pyrimidine derivatives as EGFR kinase inhibitors. …”

Section: 1egfrmentioning

confidence: 99%

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

Elrazaz

Serya

Ismail

et al. 2015

Future Journal of Pharmaceutical Sciences

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Please cite this article as: Elrazaz EZ, Serya RAT, Ismail NSM, Abou El Ella DA, Abouzid KAM, Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents, Future Journal of Pharmaceutical sciences (2015), AbstractThienopyrimidines are fused heterocyclic ring systems; structurally resemble purines, exerting pharmacological potential in different aspects. They are known to play a crucial role in various disease conditions. Thieno[2,3-d]pyrimidine derivatives have been explored fortheir inhibitory activities towards various protein kinase enzymes. The present review is a compilation on chemical synthesis and biological anticancer significance, via inhibition of specific protein kinase enzymes, including structure-activity relationships of thieno[2,3-d]pyrimidines derivatives reported to date.

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Section: 1egfrmentioning

confidence: 99%

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

Elrazaz

Serya

Ismail

et al. 2015

Future Journal of Pharmaceutical Sciences

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“…The development of specific inhibitors to target drugresistant EGFR mutants has become an important focus for the pharmaceutical management of NSCLC patients. Recently, novel inhibitors with increased selectivity against the EGFR T790M mutant have been identified (Engelman et al, 2007;de La Motte Rouge et al, 2007;Li et al, 2008;Cha et al, 2009Cha et al, , 2011Zhou et al, 2009Zhou et al, , 2011Carmi et al, 2010;Wu et al, 2010;Kobayashi et al, 2012;Taube et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor

et al. 2012

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The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.

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“…To measure the activity of the compounds in inhibiting EGFR kinase activity, the expressions of wild-type (WT) and double-mutation (DM) EGFR kinases were determined as described previously4647. Briefly, the expression constructs GST-EGFR-KDWT containing the kinase domain of human EGFR (amino acids 696–1,022) and GST-EGFR-KD L858R/T790M containing the kinase domain of EGFR with the T790M and L858R mutations were expressed in Sf9 insect cells.…”

Section: Methodsmentioning

confidence: 99%

Anchor-based classification and type-C inhibitors for tyrosine kinases

Hsu

Sung

Lin

et al. 2015

Sci Rep

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Tyrosine kinases regulate various biological processes and are drug targets for cancers. At present, the design of selective and anti-resistant inhibitors of kinases is an emergent task. Here, we inferred specific site-moiety maps containing two specific anchors to uncover a new binding pocket in the C-terminal hinge region by docking 4,680 kinase inhibitors into 51 protein kinases, and this finding provides an opportunity for the development of kinase inhibitors with high selectivity and anti-drug resistance. We present an anchor-based classification for tyrosine kinases and discover two type-C inhibitors, namely rosmarinic acid (RA) and EGCG, which occupy two and one specific anchors, respectively, by screening 118,759 natural compounds. Our profiling reveals that RA and EGCG selectively inhibit 3% (EGFR and SYK) and 14% of 64 kinases, respectively. According to the guide of our anchor model, we synthesized three RA derivatives with better potency. These type-C inhibitors are able to maintain activities for drug-resistant EGFR and decrease the invasion ability of breast cancer cells. Our results show that the type-C inhibitors occupying a new pocket are promising for cancer treatments due to their kinase selectivity and anti-drug resistance.

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Design and Synthesis of Tetrahydropyridothieno[2,3-d]pyrimidine Scaffold Based Epidermal Growth Factor Receptor (EGFR) Kinase Inhibitors: The Role of Side Chain Chirality and Michael Acceptor Group for Maximal Potency

Cited by 106 publications

References 18 publications

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

Thieno[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents

Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor

Anchor-based classification and type-C inhibitors for tyrosine kinases

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