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Cited by 594

The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.

Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

Open access
Johnson, Ted W., Richardson, Paul F., Bailey, Simon, Brooun, Alexei, Burke, Benjamin J., Collins, Michael R., Cui, J. Jean, Deal, Judith G., Deng, Ya-Li, Dinh, Dac, Engstrom, Lars D., He, Mingying, Hoffman, Jacqui, Hoffman, Robert L., Huang, Qinhua, Kania, Robert S., Kath, John C., Lam, Hieu, Lam, Justine L., Le, Phuong T., Lingardo, Laura, Liu, Wei, McTigue, Michele, Palmer, Cynthia L., Sach, Neal W., Smeal, Tod, Smith, Graham L., Stewart, Albert E., Timofeevski, Sergei, Zhu, Huichun, Zhu, Jinjiang, Zou, Helen Y., Edwards, Martin P.·2014·Journal of Medicinal Chemistry
DOI 10.1021/jm500261q
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Abstract

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

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Metadata

Authors
Johnson, T. W., Richardson, P. F., Bailey, S., Brooun, A., Burke, B. J., Collins, M. R., Cui, J. J., Deal, J. G., Deng, Y.-L., Dinh, D., Engstrom, L. D., He, M., Hoffman, J., Hoffman, R. L., Huang, Q., Kania, R. S., Kath, J. C., Lam, H., Lam, J. L., Le, P. T., Lingardo, L., Liu, W., McTigue, M., Palmer, C. L., Sach, N. W., Smeal, T., Smith, G. L., Stewart, A. E., Timofeevski, S., Zhu, H., Zhu, J., Zou, H. Y., & Edwards, M. P.
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2014-06-03
Volume
57
Issue
11
Pages
4720-4744
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/jm500261q
OpenAlex
W2784414491
Cited by
594
References
62
FWCI
30.53
Type
journal article
Language
en
Open access
green

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CoChat. (2026). Citation check: Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations. https://app.cochat.ai/papers/10.1021/jm500261q
The paper
Johnson, T. W., Richardson, P. F., Bailey, S., Brooun, A., Burke, B. J., Collins, M. R., Cui, J. J., Deal, J. G., Deng, Y.-L., Dinh, D., Engstrom, L. D., He, M., Hoffman, J., Hoffman, R. L., Huang, Q., Kania, R. S., Kath, J. C., Lam, H., Lam, J. L., . . . Edwards, M. P. (2014). Discovery of (10 R )-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H -8,4-(metheno)pyrazolo[4,3- h ][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm500261q

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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.