Abstract
Epidermal growth factor receptor (EGFR) upregulations are found in many types of cancers, including breast cancer, cholangiocarcinoma, ovarian cancer, prostate cancer, leukemia, and colon cancer. This Patent Highlight showcases PROTAC compounds formed by conjugating EGFR inhibitor with E3 ligase ligand, which recruit targeted proteins to E3 ubiquitin ligase for EGFR mutant protein degradation.
Important Compound Classes
Title
EGFR Degraders and Methods of Use
Patent Publication Number
WO 2022/171123 A1 (URL: https://patents.google.com/patent/WO2022171123A1/en?oq=WO+2022%2f171123+A1)
Publication Date
August 18, 2022
Priority Application
PCT/CN2021/076500
Priority Date
February 10, 2021
Inventors
Lei, B.; Liu, H.; Han, S.; Wang, Z.
Assignee Company
Beigene, Ltd. [GB/GB]; c/o Mourant Governance Services (Cayman) Limited, 94 Solaris Avenue, Camana Bay, Grand Cayman, KY1-1108
Disease Area
Cancer
Biological Target
Epidermal growth factor receptor (EGFR)
Summary
In 2022, the American Cancer Society estimates there will be 236,740 new cases of lung cancer, resulting in appropriately 55% of deaths and making it the leading cause of cancer mortality in the United States (https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html, accessed Oct 23, 2022). Non-small-cell lung cancer (NSCLC) accounts for the majority of these cases (80–84%), and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are oncogenic drivers in a subset of this disease (adenocarcinoma). In contrast, approximately 13% of all lung cancer cases are small-cell lung cancer (SCLC). The most common EGFR-activating mutations in NSCLC are deletions in exon 19 of the EGFR gene and a single-point mutation in exon 21. EGFR is a member of the ErbB family of the receptor tyrosine kinases, and its upregulations are found in many other types of cancers, including breast cancer, cholangiocarcinoma, ovarian cancer, prostate cancer, leukemia, and colon cancer. The overexpression of EGFR activates pro-oncogenic downstream signaling pathways such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK. Consequently, these pathways play key roles in oncogenesis-related events, including cell survival, cell proliferation, cell differentiation, cellular apoptosis, and metastasis. Tyrosine kinase inhibitors (TKIs) developed over the past two decades that target mutated EGFR in treating patients with EGFR-positive NSCLC are now the standard of care over chemotherapy.
The first-generation EGFR TKIs developed for NSCLC were reversible ATP-competitive inhibitors such as gefitinib; however, after 1–2 years patients experienced a recurrence of disease due to acquired resistance to these inhibitors. The most common acquired resistance is the formation of a secondary mutation to the gatekeeper residue (T790M), which is also the prevailing acquired resistance mechanism to afatinib (an irreversible second-generation EGFR inhibitor). In addition to acquired resistance, these inhibitors suffer from limited therapeutic windows and toxicity attributed to the wild-type EGFR inhibition. Cancer cells that develop resistance to EGFR-mediated inhibition have shown increased expression of c-MET and/or altered c-MET-mediated signaling activity. In a similar manner, prolonged exposure of cancer cells to c-MET inhibitors has led to resistance through EGFR signaling. EGFR-targeting proteolysis targeting chimeras (PROTACs) offer a potential strategy to overcome drug resistance mediated by various mutants. A number of EGFR-targeting PROTACs designed to degrade EGFR mutant proteins are based on either the first, second, or third generations of EGFR inhibitors, and rare data shows EGFR-targeting PROTACs that degrade all the main EGFR mutations.
A PROTAC consists of two covalently linked protein-binding molecules, one of which has the capacity of engaging an E3 ubiquitin ligase and the other binds to the targeted protein of interest (POI) for degradation. Recruitment of the E3 ligase to the targeted proteins result in ubiquitination and subsequent degradation of the target protein by the proteasome. The E3 ubiquitin ligase (ubiquitin ligase) directly catalyzes the transfer of ubiquitin from the E2 to the target protein for degradation. The human genome encodes over 600 putative E3 ligases; however, only a limited number of E3 ubiquitin ligases (such as cereblon, Von Hippel–Lindau, mouse double minute 2 homologue, and cellular inhibitor of apoptosis protein) have been widely applied in the small-molecule PROTAC technology.
This Patent Highlight showcases PROTAC compounds and their derivatives formed by conjugating EGFR inhibitor moieties with E3 ligase ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for EGFR mutant protein degradation.
Key Structures
Biological Assay
Homogeneous time-resolved fluorescence (HTRF) assay
Biological Data
The table below shows Dmax, the maximum
percentage of inhibition (degradation).
The author declares no competing financial interest.
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