A non-conserved histidine residue on KRAS drives paralog selectivity of the KRAS G12D inhibitor MRTX1133
Keats, M. A.; Han, J. J. W.; Lee, Y.-H.; Lee, C.-S.; Luo, J.
Show abstract
The discovery of small molecule inhibitors against mutant KRAS protein was a recent breakthrough in targeted therapy. Understanding the mechanism of selectivity by KRAS inhibitors and the mechanism of resistance to them can guide the future development of KRAS inhibitors. MRTX1133 was the first non-covalent inhibitor against the KRAS G12D mutant that demonstrated specificity and potency in pre-clinical tumor models. We used isogenic cell lines expressing a single RAS allele to evaluate the selectivity of this compound. We found that in addition to KRAS G12D, MRTX1133 shows significant activity against several other KRAS mutants as well as wildtype KRAS protein. In contrast, MRTX1133 exhibits no activity against both G12D and wildtype forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 towards KRAS is associated with its binding to histidine 95 on KRAS, a residue that is not conserved in HRAS and NRAS. Reciprocal mutation of amino acid 95 among the three RAS paralogs resulted in reciprocal change in their sensitivity towards MRTX1133. Thus, histidine 95 is an essential selectivity handle for MRTX1133 towards KRAS. This knowledge could aid the development of future KRAS-selective inhibitors.
Matching journals
The top 14 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- RAF inhibitors activate the integrated stress response by direct activation of GCN2 94%
- Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells 94%
- An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer 93%
Similar papers in this journal
- An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression 93%
- Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor 93%
- Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer 93%
Similar papers in this journal
- DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma 94%
- Ras protein abundance correlates with Ras isoform mutation patterns in cancer. 93%
- Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53 93%
Similar papers in this journal
- Inhibition of tumor growth by a novel engineered chimeric toxin that cleaves activated mutant and wild-type RAS 94%
- SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status 94%
- CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors. 93%
Similar papers in this journal
- Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp13 Helicase 92%
- Identification of SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of the nsp14 RNA Cap Methyltransferase 92%
- Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp12/7/8 RNA-dependent RNA Polymerase 91%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.