Related Experiment Video

Updated: Sep 20, 2025

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

11.0K

Advances in MLKL-targeted inhibitors and PROTACs for necroptosis therapeutics

Pengcheng Dai1, Yufeng Xin1, Xiuting Qin2

  • 1School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.

Bioorganic & Medicinal Chemistry
|May 23, 2025
PubMed

Insights

This review covers new necroptosis inhibitors and degraders targeting MLKL (mixed lineage kinase domain-like protein). It details compound optimization, structural changes, and PROTAC applications for therapeutic development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Necroptosis is a regulated cell death pathway crucial in physiology and disease.
  • Mixed lineage kinase domain-like protein (MLKL) is the key effector in necroptosis.
  • MLKL's role in diseases makes it a significant therapeutic target.

Purpose of the Study:

  • To review recent advancements in MLKL-targeting necroptosis inhibitors and degraders.
  • To analyze the structural characteristics and biological activities of these compounds.
  • To provide insights for future drug development in necroptosis.

Main Methods:

  • Literature review of recent studies on MLKL inhibitors and degraders.
  • Analysis of compound optimization and structural modifications.
  • Evaluation of proteolysis-targeting chimeras (PROTACs) in MLKL targeting.

Main Results:

  • Recent progress in developing small molecule inhibitors and degraders of MLKL.
  • Successful optimization and structural modification of active compounds.
  • Emerging applications of PROTACs for targeted MLKL degradation.

Conclusions:

  • MLKL-targeting agents represent a promising therapeutic strategy for diseases involving necroptosis.
  • Understanding structure-activity relationships is key for designing effective inhibitors and degraders.
  • PROTAC technology offers novel approaches for modulating MLKL activity.
Keywords:
DegradersInhibitorsMLKLNecroptosis

More Related Videos

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines05:33

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

10.1K
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.4K

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...
7.8K
Necrosis01:16

Necrosis

Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
4.9K
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...
6.9K
Overview of Cell Death01:30

Overview of Cell Death

Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
7.9K
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
6.7K