KRAS Oncogene Connect
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4yr
Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216

Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216

Source : https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01832

Immunomodulatory drugs are a class of drugs approved for the treatment of multiple myeloma. These compounds exert their clinical effects by inducing interactions between the CRL4CRBN E3 ubiquitin ligase and...



Conclusion/Relevance: We used FPFT-2216 as a starting point for a focused medicinal chemistry campaign and developed TMX-4100 and TMX-4116, which exhibit greater selectivity for degrading PDE6D and CK1α, respectively. We also showed that the region in PDE6D that interacts with the FPFT-2216 derivatives is not the previously pursued...

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4yr
RAS-Driven Macropinocytosis of Albumin or Dextran Reveals Mutation-Specific Target Engagement of RAS p.G12C Inhibitor ARS-1620 by NIR-Fluorescence Imaging - PubMed

RAS-Driven Macropinocytosis of Albumin or Dextran Reveals Mutation-Specific Target Engagement of RAS p.G12C Inhibitor ARS-1620 by NIR-Fluorescence Imaging - PubMed

Source : https://pubmed.ncbi.nlm.nih.gov/34905147/

doi: 10.1007/s11307-021-01689-8. Online ahead of print. 1 Department of Cancer Systems Imaging, The University of Texas, M. D. Anderson Cancer Center, Unit 1907, 1515 Holcombe Blvd., Houston, TX, 77030, USA....


Conclusions: These data provide a novel approach using NIR-labeled human serum albumin to identify and monitor RAS-driven tumors as well as evaluate the on-target efficacy in vivo of inhibitors, such as ARS-1620.

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4yr
Targeting Mutated KRAS Genes to Treat Solid Tumours - PubMed

Targeting Mutated KRAS Genes to Treat Solid Tumours - PubMed

Source : https://pubmed.ncbi.nlm.nih.gov/34914038/

Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently...


Conclusion/Relevance: In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.

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4yr
Untangling the KRAS mutated lung cancer subsets and its therapeutic implications - Molecular Biomedicine

Untangling the KRAS mutated lung cancer subsets and its therapeutic implications - Molecular Biomedicine

Source : https://link.springer.com/article/10.1186/s43556-021-00061-0

The Kirsten rat sarcoma virus transforming protein (KRAS) mutations (predominate in codons 12, 13, and 61) and genomically drive nearly one-third of lung carcinomas. These mutations have complex functions in...


Relevance: We summarize the existing knowledge of KRAS mutations and their coexisting mutations that is relevant to lung cancer treatment, in this review.

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4yr
Leveraging the therapeutic potential of KRAS-G12C inhibitors

Previous strategies to indirectly target KRAS have failed in clinical trials; however, newer drugs are able to directly inhibit KRAS-G12C by selectively forming a covalent bond with cysteine 12 within the switch-II pocket of KRAS-G12C protein, thus forcing KRAS in the inactive state to cease cell proliferation. Of particular interest is that the specificity of this mechanism of action likely reduces associated toxicity.



Clinical trials focusing on combination treatments involving KRAS-G12C inhibitors are at the fore. The rationale for such trials is partly based on outcomes of in vitro or mouse trials involving the addition of agents such as mTOR and IGF1R inhibitors to boost the activity of KRAS-G12C inhibitors against KRAS-G12C mutant lung cancer cells. Combination with MEK inhibitors is another strategy, which is notable because MEK inhibitors are considered too toxic for use on their own.



Combining KRAS-G12C inhibitors with other agents is hypothesized to attain more durable and significant responses. What combinations do you think may be of potential clinical utility and why?


  • 4yr
    Combining KRAS inhibitors with SHP2 inhibitors may help in enhancing the effect or RTK inhibitors. Using MTORs can be complimentary as another pathway is inhibited simultaneously. RAF pathway is further Show More
  • 4yr
    I agree: potentially use combinations of KRAS-G12C inhibitors would be with checkpoint inhibitors, cytotoxic chemotherapy, and radiotherapy.

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