Related Experiment Video

Updated: Oct 11, 2025

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

18.3K

Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase

Benjamin J Reisman1,2, Hui Guo3,4, Haley E Ramsey5

  • 1Department of Chemistry, Vanderbilt University, Nashville, TN, USA.

Nature Chemical Biology
|December 3, 2021
PubMed

Insights

Apoptolidin A targets the F1 subcomplex of mitochondrial ATP synthase, inhibiting cancer cell growth. This discovery offers a new therapeutic strategy for oxidative phosphorylation-dependent cancers.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Biology

Background:

  • Cancer cells possess distinct bioenergetic needs.
  • Apoptolidin glycomacrolides show selective toxicity to cancer cells, but their mechanism is unknown.

Purpose of the Study:

  • To elucidate the molecular mechanism of apoptolidin A's anti-cancer activity.
  • To identify the specific molecular target of apoptolidin A.

Main Methods:

  • Photoaffinity labeling to identify target proteins.
  • Cryogenic electron microscopy (cryo-EM) for structural analysis.
  • Deep mutational scanning and CRISPR-Cas9 for functional validation.

Main Results:

  • Mitochondrial ATP synthase F1 subcomplex identified as the direct target of apoptolidin A.
  • Cryo-EM revealed a novel shared inhibition mechanism between apoptolidin and ammocidin.
  • In vivo studies demonstrated ammocidin A suppresses leukemia with minimal toxicity.

Conclusions:

  • The study defines the mechanism of action for apoptolidin family glycomacrolides.
  • Identified ATP synthase as a target provides a new avenue for treating oxidative phosphorylation-dependent cancers.

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

328
Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype14:51

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Published on: June 17, 2022

3.3K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.9K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.0K
Drugs that Destabilize Microtubules01:10

Drugs that Destabilize Microtubules

Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
2.1K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.2K
Antimicrobial Proteins01:23

Antimicrobial Proteins

Antimicrobial proteins are important components of the immune system. They aid the body in combating pathogens by either killing them directly or hindering their replication processes. Four main types of antimicrobial substances are interferons, the complement system, iron-binding proteins, and antimicrobial proteins.
Interferons
Interferons (IFNs) are proteins produced by lymphocytes, macrophages, and fibroblasts infected with viruses. While IFNs cannot prevent viruses from entering and...
9.0K
Targets for Drug Action: Overview01:26

Targets for Drug Action: Overview

Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
7.9K