Abstract
Provided herein are novel combination of allosteric and orthosteric EGFR inhibitors, pharmaceutical compositions, use of such compounds in treating non-small-cell lung cancer, and processes for preparing such compounds.
Important Compound Classes
Title
Combination of Allosteric and Orthosteric EGFR Inhibitors for the Treatment of Cancer
Patent Publication Number
WO 2023/217924 A1
Publication Date
November 16, 2023
Priority Applications
EP 22173211.8 and EP 22175302.3
Priority Dates
May 13, 2022, and May 25, 2022
Inventors
Jaeschke, G.; Martoglio, B.; Nagel, Y. A.; Obst-Sander, C. U.; Ricci, A.
Assignee Company
F. Hoffmann-La Roche AG, Switzerland, and F. Hoffmann-La Roche Inc., USA
Disease Area
Non-small-cell lung cancer (NSCLC)
Biological Target
Epidermal growth factor receptor (EGFR)
Summary
The HER family receptor tyrosine kinases are mediators of cell growth, differentiation, and survival. The receptor family includes four distinct members, i.e., epidermal growth factor receptor (EGFR, ErbB1, or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Upon ligand binding, the receptors form homo- and heterodimers, and subsequent activation of the intrinsic tyrosine kinase activity leads to receptor autophosphorylation and the activation of downstream signaling molecules. Deregulation of EGFR by overexpression or mutation has been implicated in many types of human cancer, including colorectal and pancreatic cancer, gliomas, head, neck, and lung cancer, and in particular non-small-cell lung cancer (NSCLC).
The present application describes a novel combination of allosteric and orthosteric EGFR inhibitors for the treatment of NSCLC. The allosteric EGFR inhibitors are given in key structures below, and the orthosteric EGFR inhibitor is Osimertinib. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
L = bond or alkylene; R1 = H or halogen;
R2 and R2′ = H and alkyl;
R3 = H, halogen or haloalkyl; R4 = alkyl or halogen; and
R5 = (heterocycloalkyl)alkylene or heterocycloalkyl.
Key Structures
Biological Assay
The EGFR homogeneous time-resolved fluorescence (HTRF) cellular assay was performed. The compounds described in this application were tested for their ability to inhibit EGFR. The EGFR IC50 values (nM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for EGFR inhibition and the biological
data obtained from testing representative examples.
Recent Review Articles
Claims
Total claims: 28
Combination claims: 16
Pharmaceutical composition claims: 1
Method of treatment claims: 1
Use of combination claims: 9
Invention claims: 1
The author declares no competing financial interest.
References
- Kato T.; Casarini I.; Cobo M.; Faivre-Finn C.; Hegi-Johnson F.; Lu S.; Ozguroglu M.; Ramalingam S. S. Lung Cancer 2024, 187, 107414 10.1016/j.lungcan.2023.107414. [DOI] [PubMed] [Google Scholar]
- Jia C.; Xu Q.; Zhao L.; Kong F.; Jia Y. Transl. Oncol. 2024, 39, 101832 10.1016/j.tranon.2023.101832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoyt K. W.; Urul D. A.; Ogboo B. C.; Wittlinger F.; Laufer S. A.; Schaefer E. M.; May E. W.; Heppner D. E. J. Med. Chem. 2024, 67, 2–16. 10.1021/acs.jmedchem.3c01502. [DOI] [PubMed] [Google Scholar]
- Cho B. C.; Simi A.; Sabari J.; Vijayaraghavan S.; Moores S.; Spira A. Clin. Lung Cancer 2023, 24, 89–97. 10.1016/j.cllc.2022.11.004. [DOI] [PubMed] [Google Scholar]
- Herrera-Juarez M.; Serrano-Gomez C.; Bote-de-Cabo H.; Paz-Ares L. Cancer 2023, 129, 1803–1820. 10.1002/cncr.34757. [DOI] [PubMed] [Google Scholar]
- Wang Z.; Zhou F.; Xu S.; Wang K.; Ding H. Cancer Med. 2023, 12, 18516–18530. 10.1002/cam4.6453. [DOI] [PMC free article] [PubMed] [Google Scholar]