Recent achievements in developing selective G_q inhibitors

Abstract

G proteins are key mediators of G protein‐coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM‐254890 and FR900359 are two of the very few known selective inhibitors of the Gq subfamily, and are used as unique pharmacological tools in the study of G q‐mediated signaling. Moreover, a peptide‐based G protein antagonist‐2A (GP‐2A), a 27‐residue peptide (27mer(I860A)) derived from phospholipase C‐β3 (PLC‐β3), and the small molecule BIM‐46187 have also been characterized as selective G q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G q inhibitors. The development and application of G q‐selective inhibitors will expand our knowledge of the structure and function of G protein‐mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer.

Tetrahydroimidazo[1,2‐a]pyrazine Derivatives: Synthesis and Evaluation as Gαq‐Protein Ligands

“…However,i nc ase of complex disorders, such as cancerorpain, which involve multiple receptors and their associated pathways, the interference at the post-receptorl evel appears to be particularly promising and the intracellular Gp roteins can thus be envisaged to serve as potentiald rug targets. [6,7] Furthermore, the direct influence on specific Gp roteins may constitute au seful pharmacological strategy to unravel their role under physiological and pathophysiological conditions. According to the amino acid sequence homology of the Ga subunits,h eterotrimeric Gp roteins are subdivided into four families, Ga s ,G a i/o ,G a q and Ga 12/13 .T he Ga q family comprises four members, that is, Ga q , Ga 11 ,G a 14 and Ga 15/16 ,a mong which the isoformsG a q and Ga 11 are mostc rucial and ubiquitously expressed.…”

“…[8,9] In their customary role, Ga q familym embers activate their major downstream effector, the enzyme phospholipase C-b (PLCb), leading to hydrolysis of membrane-bound phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol(DAG), whichi nt urn activates protein kinase C, and into myo-inositol 1,4,5-trisphosphate (IP3), which initiates the release of calcium ions from the endoplasmic or sarcoplasmic reticulumi nto the cytosol by opening IP3-sensitive calcium channels. [7,8] The modulation of the Ga q proteins ubfamilyi so fp articular relevance, since its members accountf or aw ide variety of cellular responses, [7,10] leadingt oi mportant physiological functions,s uch as platelet aggregation, [11] insulin-stimulated glu-cose transport, [12] as well as pathophysiological consequences, such as heart failure, [13] and cancer. [6,9,14] Hence, selective and potent modulators are highly required as tool compounds to investigate Gp rotein-mediated signaling or as feasible drug candidates.…”

“…Prominent modulators of Ga q proteins include, on the one hand, isolatedn atural products, YM-254890 and FR900359, and on the other hand, molecules gained from organic syntheses, the BIM molecules (BIM-46174 and BIM-46187)a nd 27-mer(I860A), all of which represent selective inhibitorsf or Ga q . [7] Amongt hese, the cyclic depsipeptidesY M-254890a nd FR900359, obtained from the fermentation broth of Chromobacterium sp. QS3666 or from the leaves of the plant Ardisia crenata sims,r espectively,exhibit extraordinary selectivity and receive exceptional attention.…”

“…QS3666 or from the leaves of the plant Ardisia crenata sims,r espectively,exhibit extraordinary selectivity and receive exceptional attention. [6][7][8][15][16] The linear peptide 27-mer(I860A), derived from the phospholipase C-b isoform PLC-b3, has also been identified as as elective Ga q inhibitor, however its molecular mechanism of action still remains unclear. [7,17] The two BIM molecules (Scheme 1) have been previously reported as pan-G protein inhibitors, correspondingt o their ability to likewisei nhibita ll of the four G-protein families.…”

“…[6][7][8][15][16] The linear peptide 27-mer(I860A), derived from the phospholipase C-b isoform PLC-b3, has also been identified as as elective Ga q inhibitor, however its molecular mechanism of action still remains unclear. [7,17] The two BIM molecules (Scheme 1) have been previously reported as pan-G protein inhibitors, correspondingt o their ability to likewisei nhibita ll of the four G-protein families. [15,18] This conclusion relied on the compounds' inhibitory interference with two second messenger pathways, the cyclic adenosine-3',5'-monophosphate (cAMP) andt he myo-inositol 1-phosphate (IP1) pathway,a se valuated in human breast cancer MCF7 and melanoma A2058 cell lines, respectively.…”