Development of second-generation indole-based dynamin GTPase inhibitors.
Christopher P Gordon1, Barbara Venn-Brown, Mark J Robertson
1Chemistry, Centre for Chemical Biology, School of Environmental and Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
Journal of Medicinal Chemistry
|November 22, 2012
Summary
Researchers identified novel indole compounds that potently inhibit dynamin GTPase, a key protein in cellular processes. Compound 24 is the most effective cell-permeable inhibitor of clathrin-mediated endocytosis discovered to date.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cell Biology
Background:
- Dynamin GTPase plays a crucial role in cellular functions, including endocytosis.
- Inhibiting dynamin GTPase is a potential therapeutic strategy for various diseases.
- Developing potent and selective dynamin inhibitors is an ongoing research challenge.
Purpose of the Study:
- To develop novel, potent, and selective inhibitors of dynamin GTPase.
- To explore structure-activity relationships of indole-based dynamin inhibitors.
- To identify compounds that effectively inhibit clathrin-mediated endocytosis in cells.
Main Methods:
- Focused library development around a lead indole scaffold.
- Chemical synthesis including flow chemistry and reductive amination.
- In vitro assays to determine IC50 values for dynamin I and II inhibition.
- Cell-based assays to measure inhibition of clathrin-mediated endocytosis (CME).
Main Results:
- The tertiary dimethylamino-propyl moiety was confirmed as critical for dynamin GTPase inhibition.
- Modification of the cyanoamide moiety led to potent inhibitors, including thiazole-4(5H)-one isosteres.
- Flow chemistry and reductive amination yielded high-potency compounds.
- Compound 24 demonstrated significant potency against dynamin I and II (IC50(dyn I) = 0.56 μM) and inhibited CME (IC50(CME) = 1.9 μM).
- Compound 24 exhibited 4.4-fold selectivity for dynamin I and was found to be nontoxic.
Conclusions:
- The indole scaffold is a promising basis for developing potent dynamin GTPase inhibitors.
- Compound 24 represents a significant advancement, showing improved isoform selectivity and potent inhibition of CME.
- This research provides a highly active, cell-permeable inhibitor for studying dynamin function and exploring therapeutic applications.
Related Concept Videos
01:28Inhibitors of Bacterial DNA Synthesis
Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
01:32Pinching-off of Coated Vesicles
Vesicle budding is orchestrated by distinct cytosolic proteins such as adaptor proteins, coat proteins, and GTPases. To initiate vesicle budding, membrane-bending proteins containing crescent-shaped BAR domains bind to the lipid heads in the bilayer and distort the membrane to form a protein-coated vesicle bud. Adaptors proteins such as AP2 for clathrin-coated vesicles can nucleate on the deformed membrane. Finally, coat proteins such as clathrin or COPI and COPII assemble into a coat forming...
02:14GTPases and their Regulation
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Large G-proteins, also known...
02:14GTPases and their Regulation
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins, also known...
Large G-proteins, also known...
01:11IP3/DAG Signaling Pathway
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
01:23Dipeptidyl Peptidase 4 Inhibitors
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...