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Updated: Jan 23, 2026

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid

Nagore I Marín-Ramos1,2, Moisés Balabasquer1, Francisco J Ortega-Nogales1

  • 1Departamento de Química Orgánica I, Facultad de Ciencias Químicas , Universidad Complutense de Madrid , E-28040 Madrid , Spain.

Journal of Medicinal Chemistry
|June 12, 2019
PubMed

Insights

A new compound, UCM-1336, effectively inhibits isoprenylcysteine carboxylmethyltransferase (ICMT), blocking Ras signaling. This novel approach shows promise for treating Ras-driven tumors by targeting a key enzyme in post-translational modification.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ras signaling pathways are crucial in cancer development.
  • Targeting Ras activity is a key strategy for cancer therapy.
  • Isoprenylcysteine carboxylmethyltransferase (ICMT) mediates Ras post-translational methylation, a potential therapeutic target.

Purpose of the Study:

  • To identify and characterize a potent and selective inhibitor of ICMT.
  • To evaluate the efficacy of the ICMT inhibitor in preclinical cancer models.
  • To validate ICMT as a therapeutic target for Ras-driven tumors.

Main Methods:

  • Synthesis and characterization of a novel ICMT inhibitor, compound 3 (UCM-1336).
  • In vitro assays to determine IC50 and selectivity against related enzymes.
  • Assessment of compound 3's effect on Ras isoform membrane association and downstream signaling.
  • Evaluation of compound 3's efficacy in Ras-mutated tumor cell lines and an in vivo acute myeloid leukemia model.

Main Results:

  • Compound 3 (UCM-1336) was identified as a potent ICMT inhibitor with an IC50 of 2 μM.
  • Compound 3 demonstrated selectivity against other Ras post-translational modification enzymes.
  • Inhibition of ICMT by compound 3 led to decreased Ras activity and downstream signaling.
  • Compound 3 induced cell death in various Ras-mutated cancer cells and improved survival in an acute myeloid leukemia model.

Conclusions:

  • Compound 3 (UCM-1336) is a potent and selective ICMT inhibitor with significant antitumor activity.
  • ICMT inhibition effectively targets Ras isoforms, overcoming limitations of existing Ras inhibitors.
  • ICMT represents a validated and promising therapeutic target for treating Ras-driven cancers.

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