Abstract
Pancreatic carcinoma-1 (PANC-1) is a human pancreatic cancer cell line derived from a pancreatic ductal adenocarcinoma (PDAC) tumor, often used in research to study pancreatic cancer biology, molecular mechanisms, and potential therapeutic interventions. PANC-1 cells exhibit genetic alterations characteristic of pancreatic cancer, such as mutations in the KRAS oncogene and TP53 tumor suppressor gene. Cultured in vitro, these cells enable researchers to investigate the effects of treatments, genetic manipulations, or signaling pathway modulations on cancer cell growth, survival, and migration. This Patent Highlight discloses new compounds capable of inhibiting KRASG12D proteins, potentially useful in treating KRASG12D-associated diseases, such as pancreatic cancer.
Important Compound Classes
Title
KRASG12D Inhibitors and Uses Thereof
Patent Publication Number
WO 2023/284537 A1
(URL: https://patents.google.com/patent/WO2023284537A1/en?oq=WO+2023%2f284537+A1)
Publication Date
January 19, 2023
Priority Applications
CN PCT/CN2021/133648
Priority Dates
November 26, 2021
Inventors
Zhou, D.; Wang, Z.; Cheng, Z.; Chen, S.
Assignee Companies
Shanghai Zion Pharma Co. Limited [CN/CN]; 8F, #805, Chamtime Tower B, 2889 Jinke Road, Pudong New District, Shanghai 200210, China
Disease Area
Cancer
Biological Target
KRASG12D
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the U.S., with approximately 57,600 new cases diagnosed in 2020, resulting in 47,050 deaths. The disease’s poor prognosis is due to its early systemic spread and aggressive local growth. Around 50–60% of patients present with distant metastatic disease, 25–30% with regional disease, and only 10–15% with local disease. Treatment and prognosis depend on the tumor’s resectability, as incomplete resection significantly impacts survival, resembling outcomes of metastatic disease.
Pancreatic carcinoma-1 (PANC-1) is a human pancreatic cancer cell line that was established from a pancreatic ductal adenocarcinoma (PDAC) tumor. Pancreatic cancer is an aggressive malignancy with poor prognosis, and PANC-1 cells are commonly used in research as a model system to study pancreatic cancer biology, molecular mechanisms, and potential therapeutic interventions. PANC-1 cells have a number of genetic alterations that are characteristic of pancreatic cancer, such as mutations in the KRAS oncogene and the tumor suppressor gene TP53. These cells can be cultured in vitro, allowing researchers to investigate the effects of various treatments, genetic manipulations, or signaling pathway modulations on cancer cell growth, survival, and migration. Studies using PANC-1 cells have contributed to a better understanding of pancreatic cancer progression, metastasis, and resistance to therapies. Furthermore, PANC-1 cells have been used to test the efficacy and safety of novel anti-cancer agents and to explore the potential of targeted therapies for pancreatic cancer. The patent application WO 2023/284537 A1 discloses novel compounds that are capable of inhibiting KRASG12D proteins. As a result, the compounds are potentially useful in the treatment of KRASG12D-associated diseases such as pancreatic cancer.
Key Structures
Biological Assays
Phospho-ERK 1/2 assay, SOS1 nucleotide exchange binding assay, and KRASG12D 3D CellTiter-Glo proliferation assay
Biological Data
The table below shows p-ERK IC50 values of the exemplary compounds.
Recent Review Articles
The author declares no competing financial interest.
References
- Kolbeinsson H. M.; Chandana S.; Wright G. P.; Chung M. Pancreatic Cancer: A Review of Current Treatment and Novel Therapies. J. Invest. Surg. 2023, 36, 2129884. 10.1080/08941939.2022.2129884. [DOI] [PubMed] [Google Scholar]
- Beutel A. K.; Halbrook C. J. Barriers and opportunities for gemcitabine in pancreatic cancer therapy. Am. J. Physiol. Cell Physiol. 2023, 324, C540. 10.1152/ajpcell.00331.2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ortega M.; Sparks J.; Lichy J.; Nava V. E. KRAS G12D mutation in Brunner gland adenoma. BMJ. Case Rep 2023, 16, e252160. 10.1136/bcr-2022-252160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lam K. K.; Wong S. H.; Cheah P. Y. Targeting the ’Undruggable’ Driver Protein, KRAS, in Epithelial Cancers: Current Perspective. Cells 2023, 12, 631. 10.3390/cells12040631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hofmann M. H.; Gerlach D.; Misale S.; Petronczki M.; Kraut N. Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants. Cancer Discov. 2022, 12, 924–937. 10.1158/2159-8290.CD-21-1331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shen H.; Lundy J.; Strickland A. H.; Harris M.; Swan M.; Desmond C.; Jenkins B. J.; Croagh D. KRAS G12D Mutation Subtype in Pancreatic Ductal Adenocarcinoma: Does It Influence Prognosis or Stage of Disease at Presentation?. Cells 2022, 11, 3175. 10.3390/cells11193175. [DOI] [PMC free article] [PubMed] [Google Scholar]