AZD4625 is a Potent and Selective Inhibitor of KRASG12C
Atanu Chakraborty1, Lyndsey Hanson1, David Robinson1
1AstraZeneca, Cambridge, United Kingdom.
Molecular Cancer Therapeutics
|August 5, 2022
Summary
AZD4625 is a potent, selective, and orally bioavailable inhibitor targeting the KRASG12C mutation. This drug shows potential for treating KRASG12C-mutant cancers as a monotherapy or in combination treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Oncogenic KRASG12C mutations are key drivers in various cancers.
- Targeting KRASG12C offers a therapeutic strategy for these malignancies.
Purpose of the Study:
- To evaluate AZD4625 as a potent and selective inhibitor of KRASG12C.
- To assess the therapeutic potential of AZD4625 in preclinical cancer models.
Main Methods:
- In vitro and cellular assays were used to determine binding and inhibition specificity.
- Preclinical studies utilized cell line-derived and patient-derived xenograft models.
Main Results:
- AZD4625 demonstrated potent and selective inhibition of the KRASG12C mutant isoform.
- No binding or inhibition was observed against wild-type RAS or other RAS isoforms.
- AZD4625 showed efficacy in preclinical xenograft models.
Conclusions:
- AZD4625 is a promising oral therapeutic agent targeting KRASG12C.
- The drug has potential for monotherapy or combination therapy in KRASG12C-mutant cancers.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
18.1K
05:29A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
2.9K
Related Concept Videos
02:38The Ras Gene
6.4K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
6.4K
03:03mTOR Signaling and Cancer Progression
3.9K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.9K
01:22PI3K/mTOR/AKT Signaling Pathway
3.9K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.9K
01:24Small GTPases - Ras and Rho
4.2K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
4.2K
02:34Inhibition of Cdk Activity
4.9K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K
02:23Abnormal Proliferation
4.6K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K