Discovery of A Novel Her-1/Her-2 Dual Tyrosine Kinase Inhibitor for the Treatment of Her-1 Selective Inhibitor-Resistant Non-small Cell Lung Cancer

Young, Mi; Lee, Kwang-Ok; Kim, Jong Woo; Lee, Chang Gon; Song, Ji Yeon; Kim, Young Hoon; Lee, Gwan Sun; Park, Seung Bum; Kim, Maeng Sup

doi:10.1021/jm901146p

Cited by 34 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EGFR WT (Upstate, Billerica/MA), EGFR T790M (Upstate, Billerica/MA), EGFR T790M/L858R (Upstate, Billerica/MA), HER‐2 (Invitrogen, Carlsbad/CA) and HER‐4 (Invitrogen, Carlsbad/CA) were expressed by baculovirus in Sf21 insect cells and used for kinase assays and IC 50 determinations, which were performed as previously described 38. To determine the selectivity of HM781‐36B against various kinases, the SelectScreen™ Kinase Profiling service was used (Invitrogen, Carlsbad/CA).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Antitumor activity of HM781‐36B, a highly effective pan‐HER inhibitor in erlotinib‐resistant NSCLC and other EGFR‐dependent cancer models

Young

Lee

Kim

et al. 2011

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in-frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781-36B. The results from this study show that HM781-36B is a potent inhibitor of EGFR in vitro, including the EGFR-acquired resistance mutation (T790M), as well as HER-2 and HER-4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781-36B treatment of EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781-36B shows an excellent efficacy in a variety of EGFR-and HER-2-dependent tumor xenograft models, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant NCI-H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, NCI-N87 gastric cancer cells, SK-Ov3 ovarian cancer cells and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781-36B is the most potent pan-HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation (EGFR T790M), breast cancer and gastric cancer.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Cells were incubated in a humidified atmosphere under 5% CO 2 except for MDA‐175 cells (CO 2 free) at 37°C. Cell growth inhibition assays and GI 50 and GI 90 determinations were performed as previously described 38…”

Section: Methodsmentioning

confidence: 99%

Antitumor activity of HM781‐36B, a highly effective pan‐HER inhibitor in erlotinib‐resistant NSCLC and other EGFR‐dependent cancer models

Young

Lee

Kim

et al. 2011

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…1 H NMR (300 MHz, CDCl 3 ) δ 10.65 (s, 1H), 8.59 (d, Cell growth inhibition assays and GI 50 determinations were performed as previously described. 28 General Procedures for the Microsomal Stability Assay. All assays were conducted in duplicate.…”

Section: N-((5-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-pyrimmentioning

confidence: 99%

Synthesis and Biological Evaluation of Pyrimidine-Based Dual Inhibitors of Human Epidermal Growth Factor Receptor 1 (HER-1) and HER-2 Tyrosine Kinases

et al. 2012

Self Cite

View full text Add to dashboard Cite

A novel series of N(4)-(3-chlorophenyl)-5-(oxazol-2-yl)pyrimidine-4,6-diamines were synthesized and evaluated as dual inhibitors of HER-1/HER-2 tyrosine kinases. In contrast to the currently approved HER-2-targeted agent (lapatinib, 1), our irreversible HER-1/HER-2 inhibitors have the potential to overcome the clinically relevant and mutation-induced drug resistance. The selected compound (19a) showed excellent inhibitory activity toward HER-1/HER-2 tyrosine kinases with selectivity over 20 other kinases and inhibited the proliferation of both cancer cell types: lapatinib-sensitive cell lines (SK-Br3, MDA-MB-175, and N87) and lapatinib-resistant cell lines (MDA-MB-453, H1781, and H1975). The excellent pharmacokinetic profiles of 19a in mice and rats led us to further investigation of a novel therapeutic agent for HER-2-targeting treatment of solid tumors, especially HER-2-positive breast/gastric cancer and HER-2-mutated lung cancer.

show abstract

Discovery of A Novel Her-1/Her-2 Dual Tyrosine Kinase Inhibitor for the Treatment of Her-1 Selective Inhibitor-Resistant Non-small Cell Lung Cancer

Cited by 34 publications

References 20 publications

Antitumor activity of HM781‐36B, a highly effective pan‐HER inhibitor in erlotinib‐resistant NSCLC and other EGFR‐dependent cancer models

Antitumor activity of HM781‐36B, a highly effective pan‐HER inhibitor in erlotinib‐resistant NSCLC and other EGFR‐dependent cancer models

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

Synthesis and Biological Evaluation of Pyrimidine-Based Dual Inhibitors of Human Epidermal Growth Factor Receptor 1 (HER-1) and HER-2 Tyrosine Kinases

Contact Info

Product

Resources

About