Farnesyltransferase inhibitors: a comprehensive review based on quantitative structural analysis

Area of Science:

• Drug Discovery and Development
• Medicinal Chemistry
• Pharmacology

Background:

• Farnesyltransferase inhibitors (FTIs) are primarily used in cancer therapy.
• Emerging research highlights FTI potential in treating Progeria, malaria, and other diseases.
• The development of novel FTIs is crucial for drug discovery programs.

Purpose of the Study:

• To review the development of novel farnesyltransferase inhibitors (FTIs).
• To analyze structural features of existing FTIs for improved drug design.
• To explore the therapeutic applications of FTIs beyond oncology.

Main Methods:

• Review of peptidomimetic and non-peptidomimetic FTI development.
• Analysis of structural requirements for FTase inhibition, including heterocycles, polar groups, and hydrophobic moieties.
• Examination of natural product-derived FTIs and their structural comparison to synthetic analogs.
• Summary of ongoing clinical studies for various FTIs in cancer and rare diseases.

Main Results:

• Structural analysis indicates a need for heterocycles or polar groups for Zn(2+) interaction and bulky hydrophobic groups for optimal binding.
• Natural products like pepticinnamin E and gliotoxin exhibit potent FTase inhibitory activity.
• Clinical trials show efficacy for tipifarnib in leukemias and lonafarnib in Progeria syndrome, improving cardiovascular and bone health.
• Several FTIs are progressing through clinical trials for diverse oncological and genetic disorders.

Conclusions:

• Quantitative structural analysis and studies on natural products offer insights for novel FTI development.
• Fragment-based analysis is essential for optimizing substituents for enhanced inhibitory activity and favorable pharmacokinetics.
• FTIs represent a versatile class of compounds with broad therapeutic potential across multiple disease areas.