Table of Contents
What drugs target Ras?
Approaches to target RAS indirectly
- SOS inhibitors.
- SHP2 inhibitors.
- Synthetic lethal screens.
- EGFR family therapies.
- MAPK pathway: RAF inhibitors.
- MAPK pathway: MEK inhibitors.
- MAPK pathway: ERK inhibitors.
What is the most common KRAS mutation in pancreatic cancer?
They are frequent drivers in lung, colorectal and pancreatic cancers. KRAS drives 32\% of lung cancers, 40\% of colorectal cancers, and 85\% to 90\% of pancreatic cancer cases. G12C, G12D and G12R are some of the most common KRAS mutations, based on the specific mutations that are present.
Why is Ras drug hard?
Activated Ras is an extremely challenging direct drug target due to the inherent difficulties in disrupting the protein:protein interactions that underlie its activation and function. Major investments have been made to target Ras through indirect routes.
Is Ras Druggable?
RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify.
What makes a target Undruggable?
In the world of drug discovery, “undruggable” targets are like the stubborn children of biology, proteins that are considered too challenging to bind with conventional molecules.
Why is KRAS Hard Target?
Specific KRAS inhibition has been difficult to accomplish due to the small size of the protein and a surface area with few deep pockets for drug interaction, but numerous agents under investigation in preclinical and clinical models have overcome this challenge by using the distinct alterations of KRAS mutant tumors to …
Is KRAS mutation curable?
KRAS mutations are the most common oncogenic alteration in all of human cancers and there are currently no effective treatments available for patients with KRAS-mutant cancers.
What is the function of the Ras protein?
Like other small GTPases, Ras proteins function as molecular switches that cycle between an inactive, GDP-bound and an active, GTP-bound state to regulate cell proliferation, differentiation, migration, and apoptosis (Downward, 1997; Marshall, 1996; McCormick, 1995; Satoh et al., 1992).
What is KRAS treatment?
Standard first-line therapy for a patient with KRAS positive lung cancer may be surgery, radiation, chemotherapy, immunotherapy or a combination based on the stage of their cancer. There is now a targeted therapy pill (also called a KRAS inhibitor) for patients with KRAS G12C.
What is targeted protein degradation?
Targeted Protein Degradation (TPD) refers to the use of heterobifunctional small molecule “Degraders”, such as PROTAC® Degraders, to achieve knockdown of target proteins within cells. These Degraders harness the ubiquitin-proteasome system to knockdown a protein of interest.