Related Experiment Video
Updated: Mar 16, 2026
Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
Non-Substrate Based, Small Molecule Inhibitors of the Human Isoprenylcysteine Carboxyl Methyltransferase
Kyle V Butler1, Kelsey Bohn2, Christine A Hrycyna2
1Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
Abstract:
Activating mutations of human K-Ras proteins are among the most common oncogenic mutations, present in approximately 30% of all human cancers. Posttranslational modifications to K-Ras guide it to the plasma membrane and disruption of this localization inhibits the growth of Ras-driven cancers. The human isoprenylcysteine carboxyl methyltransferase (hIcmt) enzyme catalyzes the final α-carboxyl methylesterification of the C-terminal farnesyl cysteine of K-Ras, which is necessary for its proper localization. Thus, hIcmt inhibition is a regarded as a promising cancer therapy. A high quality inhibitor of hIcmt with in vivo activity would advance hIcmt research and drug development. Herein, Wwe report the results of a screen for small molecule hIcmt inhibitors in a library of molecules that were not hIcmt substrate analogs. The lead compound identified by this screen (1) was modified to remove chemical liabilities and to increase potency. The most potent resulting compound (5) inhibited hIcmt in vitro with low micromolar potency (IC50 = 1.5 ± 0.2 μM) and was kinetically characterized as a competitive inhibitor for prenylated substrates and a non-competitive inhibitor for the cofactor and methyl donor S-adenosylmethionine (SAM). These inhibitors offer important structure activity relationships for the future development of hIcmt inhibitors with in vivo activity.
Insights
Researchers identified novel small molecule inhibitors of human isoprenylcysteine carboxyl methyltransferase (hIcmt). These compounds target K-Ras localization, a key factor in cancer growth, offering potential for new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Activating mutations in human K-Ras proteins are prevalent in ~30% of human cancers.
- K-Ras localization to the plasma membrane, guided by posttranslational modifications, is crucial for cancer growth.
- Human isoprenylcysteine carboxyl methyltransferase (hIcmt) catalyzes a key step in K-Ras localization, making it a therapeutic target.
Purpose of the Study:
- To identify and develop novel small molecule inhibitors of hIcmt.
- To discover compounds that disrupt K-Ras localization as a cancer therapy strategy.
- To establish structure-activity relationships for future in vivo active hIcmt inhibitors.
Main Methods:
- Screening of a small molecule library for hIcmt inhibitors (non-substrate analogs).
- Chemical modification of a lead compound to improve potency and reduce liabilities.
- In vitro biochemical assays to determine inhibitor potency (IC50) and kinetic mechanism.
Main Results:
- A lead hIcmt inhibitor (compound 1) was identified from the screen.
- Optimization yielded a potent inhibitor (compound 5) with IC50 = 1.5 ± 0.2 μM.
- Compound 5 exhibited competitive inhibition kinetics with respect to prenylated substrates and non-competitive with respect to SAM.
Conclusions:
- Novel non-substrate analog hIcmt inhibitors were developed.
- The most potent inhibitor (compound 5) provides valuable structure-activity insights.
- These findings advance the development of hIcmt inhibitors for cancer therapy.
Related Concept Videos
01:19Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
01:30The Electron Transport Chain
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...