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Title: Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

Authors:
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  1. Genentech
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1228094
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 58; Journal Issue: (22) ; 11, 2015
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Heald, Robert, Bowman, Krista K., Bryan, Marian C., Burdick, Daniel, Chan, Bryan, Chan, Emily, Chen, Yuan, Clausen, Saundra, Dominguez-Fernandez, Belen, Eigenbrot, Charles, Elliott, Richard, Hanan, Emily J., Jackson, Philip, Knight, Jamie, La, Hank, Lainchbury, Michael, Malek, Shiva, Mann, Sam, Merchant, Mark, Mortara, Kyle, Purkey, Hans, Schaefer, Gabriele, Schmidt, Stephen, Seward, Eileen, Sideris, Steve, Shao, Lily, Wang, Shumei, Yeap, Kuen, Yen, Ivana, Yu, Christine, Heffron, Timothy P., and Argenta). Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.5b01412.
Heald, Robert, Bowman, Krista K., Bryan, Marian C., Burdick, Daniel, Chan, Bryan, Chan, Emily, Chen, Yuan, Clausen, Saundra, Dominguez-Fernandez, Belen, Eigenbrot, Charles, Elliott, Richard, Hanan, Emily J., Jackson, Philip, Knight, Jamie, La, Hank, Lainchbury, Michael, Malek, Shiva, Mann, Sam, Merchant, Mark, Mortara, Kyle, Purkey, Hans, Schaefer, Gabriele, Schmidt, Stephen, Seward, Eileen, Sideris, Steve, Shao, Lily, Wang, Shumei, Yeap, Kuen, Yen, Ivana, Yu, Christine, Heffron, Timothy P., & Argenta). Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study. United States. doi:10.1021/acs.jmedchem.5b01412.
Heald, Robert, Bowman, Krista K., Bryan, Marian C., Burdick, Daniel, Chan, Bryan, Chan, Emily, Chen, Yuan, Clausen, Saundra, Dominguez-Fernandez, Belen, Eigenbrot, Charles, Elliott, Richard, Hanan, Emily J., Jackson, Philip, Knight, Jamie, La, Hank, Lainchbury, Michael, Malek, Shiva, Mann, Sam, Merchant, Mark, Mortara, Kyle, Purkey, Hans, Schaefer, Gabriele, Schmidt, Stephen, Seward, Eileen, Sideris, Steve, Shao, Lily, Wang, Shumei, Yeap, Kuen, Yen, Ivana, Yu, Christine, Heffron, Timothy P., and Argenta). 2016. "Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study". United States. doi:10.1021/acs.jmedchem.5b01412.
@article{osti_1228094,
title = {Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study},
author = {Heald, Robert and Bowman, Krista K. and Bryan, Marian C. and Burdick, Daniel and Chan, Bryan and Chan, Emily and Chen, Yuan and Clausen, Saundra and Dominguez-Fernandez, Belen and Eigenbrot, Charles and Elliott, Richard and Hanan, Emily J. and Jackson, Philip and Knight, Jamie and La, Hank and Lainchbury, Michael and Malek, Shiva and Mann, Sam and Merchant, Mark and Mortara, Kyle and Purkey, Hans and Schaefer, Gabriele and Schmidt, Stephen and Seward, Eileen and Sideris, Steve and Shao, Lily and Wang, Shumei and Yeap, Kuen and Yen, Ivana and Yu, Christine and Heffron, Timothy P. and Argenta)},
abstractNote = {},
doi = {10.1021/acs.jmedchem.5b01412},
journal = {Journal of Medicinal Chemistry},
number = (22) ; 11, 2015,
volume = 58,
place = {United States},
year = 2016,
month = 7
}
  • Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. Here in this paper, wemore » describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.« less
  • Purpose: To establish the safety profile and efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) concurrent with individualized radiotherapy (RT) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Patients and Methods: Between June 2007 and January 2010, 26 patients with Stage III/IV NSCLC were enrolled in this prospective study. These patients were treated with EGFR-TKIs (gefitinib 250 mg or erlotinib 150 mg, oral daily) concurrent with individualized RT with curative intent. The thoracic RT plans were individually designed on the basis of tumor size and normal tissue volume constraints. All patients were assessed for toxicity,more » and 25 patients were available for efficacy. The primary endpoints were acute toxicity, overall survival, and median survival time. The secondary endpoints included local control rate, time to tumor progression, and progression-free survival (PFS). Results: Median gross tumor volume, mean lung dose, and lung V20 were 56 cm{sup 3}, 8.6 Gy, and 14%, respectively. Median thoracic radiation dose was 70 Gy at a margin of gross tumor volume (range, 42-82 Gy), and median biological equivalent dose was 105 Gy (range, 60-119 Gy). Acute skin, hematologic, esophageal, and pulmonary toxicities were acceptable and manageable. Severe adverse events included neutropenia (Grade 4, 4%) and thrombocytopenia (Grade 4, 8%), esophagitis (Grade 3, 4%), and pneumonitis (Grade 3, 4%). With a median follow-up of 10.2 months, a local control rate of 96% was achieved for thoracic tumor. Median time to progression, median PFS, and median survival time were 6.3, 10.2, and 21.8 months, respectively. The 1- and 2-year PFS rates were both 42%, and 1-, 2-, and 3-year overall survival rates were 57%, 45%, and 30%, respectively. Conclusion: Concurrent EGFR-TKIs with individualized RT shows a favorable safety profile and promising outcome, therefore serving as a therapeutic option for patients with locally advanced or metastatic NSCLC.« less
  • The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.
  • A mutant clone (MO-5) was originally isolated as a clone resistant to Na/sup +//K/sup +/ ionophoric antibiotic monensin from mouse Balb/c3T3 cells. MO-5 was found to show low receptor-endocytosis activity for epidermal growth factor (EGF):binding activity for EGF in MO-5 was less than one tenth of that in Balb/c3T3. Anchorage-independent growth of MO-5 was compared to that of Balb/c3T3 when assayed by colony formation capacity in soft agar. Coadministration of EGF and TGF-..beta.. efficiently enhanced anchorage-independent growth of normal rat kidney (NRK) cells, but neither factor alone was competent to promote the anchorage-independent growth. The frequency of colonies appearing inmore » soft agar of MO-5 or Balb/c3T3 was significantly enhanced by TGF-..beta.. while EGF did not further enhance that of MO-5 or Balb/c3T3. Colonies of Balb/c3T3 formed in soft agar in the presence of TGF-..beta.. showed low colony formation capacity in soft agar in the absence of TGF-..beta... Colonies of MO-5 formed by TGF-..beta.. in soft agar, however, showed high colony formation capacity in soft agar in the absence of TGF-..beta... Pretreatment of MO-5 with TGF-..beta.. induced secretion of TGF-..beta..-like activity from the cells, while the treatment of Balb/c3T3 did not induce the secretion of a significant amount of TGF-..beta..-like activity. The loss of EGF-receptor activity in the stable expression and maintenance of the transformed phenotype in MO-5 is discussed.« less