Post-translational Modification

Post-translational modification (PTM) is the chemical modification of a protein after its creation (translation). This modification can affect protein behavior such as gene expression. Post-translational modifications include phosphorylation, glycosylation, acetylation, methylation, ubiquitylation, and sulfation. After protein synthesis, PTM increases the range of protein function by attaching it to other proteins or to other functional groups like acetate, phosphate, various lipids, and carbohydrates. PTMs regulate cellular activity and occur at distinct amino acid side chains or peptide linkages. They are most often mediated by enzymatic activity and can be reversible depending on the nature of the modification.

Sigma provides several compounds to study the pivotal role of PTMs in normal cell biology and diseases where multiple genes are involved, such as heart disease, cancer, neurodegenerative diseases, and diabetes.

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SML1805 APS-2-79 hydrochloride ≥98% (HPLC) APS-2-79 is a stabilizer of the Kinase suppressor of Ras (KSR) inactive state, resulting in inhibition of oncogenic Ras signaling, antagonizing the Ras–MAPK pathway. KSR is a MAPK scaffold that is regulated allosterically by dimerization with RAF. APS-2-79 was found to bind to the KSR active site with an IC50 value of 120 nM, antagonizing MEK (MAPKK) phosphorylation by RAF. In Ras mutant cell lines, APS-2-79 increased the potency of several MEK inhibitors..
SML1570 Arglabin ≥98% (HPLC) Arglabin is a natural product with antitumor and anti-inflammatory activity. Arglabin competitively inhibits the binding of farnesyl diphosphate to farnesyl transferase (FTase), preventing the activation of RAS proto-oncogene by preventing the incorporation of farnesyl pyrophosphate into human H-ras proteins. Arglabin is also an inhibitor of the NLRP3 inflammasome. Arglabin reduces inflammation and plasma lipids and has shown a marked reduction in atherosclerotic lesions.
B2559 B581 >95% (HPLC), solid Stable and membrane permeable inhibitor of farnesyltransferase.
SML1268 BQU57 ≥98% (HPLC) BQU57 is a selective inhibitor of the Ras-like GTPases RalA and RalB, downstream mediators of Ras signalling, without direct inihibition of Ras or RhoA activity . BQU57 binds to a site on the GDP-bound form of Ral, its inactive state, inhibiting the binding of Ral to its effectors, such as Ral-binding protein 1 (RALBP1; also known as RLIP760, which are involved in proliferation, survival, and metastasis of several human cancers. BQU57 inhibited growth in human luung cancer cell lines with IC50 values of 2.0 μM in H2122 cells and 1.3 μM in H358 cells, and also inihbited tumor xenograft growth.
SML1253 CASIN ≥98% (HPLC) CASIN is an inhibitor of Cdc42 GTPase, a small GTPase of the Rho-subfamily that plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. CASIN generated a rejuvenated phenotype of Hematopoietic stem cells (HSCs), reversing the aging-related and polarity phenotype of aged HSCs to that of young HSCs in vivo..
SML0987 CCG-1423 ≥98% (HPLC) CCG-1423 is a potent and specific inhibitor of Rho pathway signaling and activation of serum response factor (SRF) transcription. CCG-1423 inhibits SRF-driven luciferase expression in PC-3 cells following stimulation with constitutively active Gα13. Also CCG-1423 selectively inhibits DNA synthesis, proliferation and invasion of Rho-overexpressing cell lines.
SML1422 CCG-203971 ≥98% (HPLC) CCG-203971 is an inhibitor of the Rho/MKL1/SRF transcriptional pathway, which has been shown to play a role in metastasis of melanoma and breast cancer and clinically associated with castration-resistant prostate cancer. CCG-203971 is a second-generation analog of CCG-1423 (SML0987) with an IC50 of 4.2 μM vs 1 μM for CCG-1423, but less cytotoxicity. In mouse studies, CCG-203971 inhibited invasion of PC-3 prostate cancer cells and was well tolerated up to doses of 100 mg/kg IP over 5 days.

The Rho/MRTF/SRF pathway has also been shown to be involved in multiple types of solid organ fibrosis. CCG-203971 repressed both matrix-stiffness and TGF-β-mediated fibrogenesis in human colonic myofibroblasts and showed antifibrotic activity in a murine model of skin injury and in pulmonary fibrosis lung fibroblasts.
SML0545 CID 1067700 ≥98% (HPLC) CID 1067700 antagonizes ras-related protein Rab-7 and reduces class switch DNA recombination (CSR) in B cells and survival of plasma cells.
CID 1067700 is a potent and competitive inhibitor of Ras-related GTPases that potently binds to Rab7 nucleotide binding site.
SML0918 CID44216842 ≥98% (HPLC) CID44216842 is a potent and selective non-competitive allosteric inhibitor of Cdc42 GTPase that does not inhabit Rho and Rac. CID44216842 inhibits Cdc42 dependent filopodia formation and cell migration.
SML1714 DCAI ≥95% (HPLC) DCAI, an Inactive Ras, is bound to a GDP and activated by SOS (son of sevenless, among others), which converts it to the active GTP form. DCAI is a known binder to Ras, which inhibits SOS nucleotide exchange, inhibiting Ras activation.
D7693 Dynasore hydrate Dynasore is a cell-permeable, reversible noncompetitive dynamin 1 and dynamin 2 GTPase activity inhibitor.
SML1006 EGA ≥98% (HPLC) EGA is a small molecule that blocks the entry of anthrax lethal toxin by inhibiting trafficking pathways in acidified endosomes, without affecting endosome pH. EGA blocks trafficking of other toxins, including diphtheria toxin, but does not inhibit trafficking of ricin. The compound EGA attenuates lysosomal targeting and degradation of the EGF receptor, but does not block does not block endosomal recycling of transferrin.
E8280 Exo 1 ≥98% (HPLC), solid Reversible inhibitor of exocytosis; Golgi ARF 1 (ADP-Ribosylation Factor) GTPase activator.
F6892 Farnesyl pyrophosphate ammonium salt methanol:ammonia solution, ≥95% (TLC) Farnesyl pyrophosphate (FPP) is the precursor for the biosynthesis of cholesterol, ubiquinone and dolicol. It is part of the intracellular mevalonate pathway. FPP is essential for cell survival and is used for prenylation of several low molecular mass G proteins, including Ras. Inhibition of prenylation results in loss of oncogenic potential of Ras proteins. Inhibition of prenylation may serve as therapeutic potential for management of synaptic plasticity and Alzheimer′s disease.
F1928 Farnesyl triphosphate ammonium salt solution ≥95% (TLC), methanol:ammonia solution  
F9803 FTI-277 trifluoroacetate salt ≥95% (HPLC), film Farnesyltransferase inhibitor 277 (FTI-277) mediates apoptosis in multiple myeloma and is regarded as a potential therapeutic agent.
Highly potent (pM/nM) Ras CAAX peptidomimetic which antagonizes both H and K-Ras oncogenic signaling. Inhibitor of farnesyltransferase (Ftase) IC50 = 50 nM.
G6025 Geranylgeranyl pyrophosphate ammonium salt solution, ≥95% (TLC), ~1 mg/mL in methanol: NH4OH (7:3) Geranylgeranyl pyrophosphate (GGPP) is a major enzyme that participates in the secondary metabolism of chloroplast. GGPP synthase plays a key role in the biosynthesis of terpenoid. Protein geranylgeranylation, mediated by geranylgeranyl pyrophosphate participates in the development of the ventricular chamber. It also serves as a stage-specific signal to modulate the formation of cardiac cytoarchitecture the time of mid-gestation.
Isoprenoid from the intracellular mevalonate pathway used for prenylation of several low molecular weight G proteins, including Ras. Intermediate in terpene biosynthesis.
G2418 Geranyl triphosphate ammonium salt solution methanol:ammonia solution  
SML1186 GGTI-286 dihydrochloride ≥90% (HPLC) GGTI-286 is a cell permeable, potent and selective inhibitor of geranylgeranyltransferase I (GGTase I) that selectively disrupts oncogenic K-Ras4B. New study shows that GGTI-286 reduces nuclear localization of β-catenin.
G0923 Golgicide A ≥98% (HPLC) Golgicide A is a potent, highly specific, reversible inhibitor of the cis-Golgi ArfGEF GBF1. Arf proteins are members of the Ras superfamily of small guanosine triphosphatases (GTPases) that mediate vesicular transport. Golgicide A binds within an interfacial cleft formed between Arf1 and the GBF1 Sec7 domain. Golgicide A is a unique and powerful tool for further elucidating the mechanisms underlying assembly and transport within the Golgi, comparable to the use of dynasore for studying the dynamics of dynamin-mediated clathrin coat formation.
SML0340 Hydroxy-Dynasore ≥98% (HPLC) Hydroxy-Dynasore is a cell permeable and potent dynamin inhibitor that prevents uptake of recombinant botulinum neurotoxin A heavy chain binding domain (BoNT/A-Hc). Apparently, Hydroxy-Dynasore prevents dynamin-mediated fission of endocytic vesicles from the plasma membrane.
I1282 Isopentenyl triphosphate ammonium salt solution ≥95% (TLC) Isoprenoid building block.
I1411 ITX3 ≥98% (HPLC) ITX3 is a specific inhibitor of endogenous TrioN activity acting on the GEF domain and selective cell active inhibitor of the Trio/RhoG/Rac1 pathway. The compound is active in whole cell assay where it inhibits the formation of TrioN-dependent cell structures. ITX3 appears to be specific for TrioN inhibition rather than other RhoGEFs.
SML1654 R-Ketorolac ≥95% (HPLC) Ketorolac ((rac)-5-benzoyl-1,2-3H-pyrrolo[1,2a] pyrrole1-carboxylic acid) is a non-steroidal anti-inflammatory drug (NSAID). It is used as a racemic mixture that contains a 1:1 ratio of the R(+) and S(−) stereoisomers. It is broadly used off-label as a parenteral analgesic in children. Ketorolac serves as a non-narcotic analgesic. It prevents the synthesis of prostaglandins, peripheral to the central nervous system.
R-Ketorolac is potent and selective Rho-family GTPases Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) allosteric inhibitor that modulates downstream GTPase-dependent physiologic responses critical to tumor metastasis. R-ketorolac significantly inhibits ovarian cancer cell adhesion, migration, and invasion.
SML0961 Kobe0065 ≥98% (HPLC) Kobe0065 binds to Ras-GTP, blocking interactions with Raf kinase. Kobe0065 inhibits anchorage-dependent and -independent growth, blocks MEK/ERK activity and induces apoptosis in H-rasG12V transformed NIH3T3 cells. The compound Kobe0065 also inhibts tumor growth in SW480 colon cancer cell xenografts.
SML1457 Lonafarnib ≥98% (HPLC) Lonafarnib is a potent inhibitor of farnesyltransferase, an enzyme responsible for a post-translational modification of proteins (including Ras) that gives a protein sufficient hydrophobicity to translocate to the plasma membrane. Farnesylation regulates signaling cascades controlling cell survival, proliferation and differentiation, so variety of possible uses is not surprising a post-translational modification of proteins (including Ras) that gives a protein sufficient hydrophobicity to translocate to the plasma membrane. Lonafarnib has been studies for possible treatment of progeria, various cancers, and hepatitis D.
Lonafarnib prevents the post-translational lipid modification of H-Ras and other farnesylated proteins. Lonafarnib treatment results in microtubule bundling, increased microtubule acetylation and stabilization and suppression of microtubule dynamics.
M6418 Manumycin A from Streptomyces parvulus Manumycin A is a natural monomeric epoxyquinoid. It has an ability to inhibit tumor necrosis factor (TNF) induced IκB kinase (IKK) activity in various cell types. In addition, manumycin A exhibits anti-tumor property by inhibiting farnesylation of oncogenic Ras.
Potent inhibitor of Ras farnesyltransferase.
SML1258 ML099 ≥98% (HPLC) ML099 is a Ras-related GTPase activator. Mutated forms of small GTPases induce proliferation and transformation of a number of cell types as well as differentiation of neuronal cells. The only known activation mechanism of small GTPase is via guanine nucleotide-exchange factors (GEFs). Data suggests that some diseases, including immunodeficienty syndromes result from loss of function mutations in the Rac2 GTPase, and the GEF cdc42. ML099 can activate cdc42, Rac1 and Ras GTPase activity with mid to high nM EC50s. GTPase activatiors could be useful tools for defining the mechanism of GEF activation of GTPases, further understanding of GTPase signaling mechanisms and study of diseases in which loss of function mutants are implicated.
M0319 MRS 2578 ≥95% (HPLC) Potent and irreversible antagonist of P2Y6 nucleotide receptor.
M4414 Myristoyl coenzyme A lithium salt ≥80.0% Myristoyl coenzyme A is a combination of coenzyme A and myristate. It serves as a substrate in protein myristoylation, catalyzed by the enzyme N-myristoyl transferase. Myristyolation involves the transfer of the myristoyl group to the glycine residue at the amino-terminal of the protein.
SML0952 NSC23766 trihydrochloride ≥97% (HPLC) NSC23766 is an inhibitor of Rac1, a Rho-family GTPase. The compound blocks activation by the guanine nucleotide exchange factors Trio and Tiam1, but does not affect interactions with RhoA or Cdc42. NSC23766 blocks ADP-mediated platelet aggregation. Inhibition of Rac1 by NSC23766 restores sensitivity to trastuzumab by restoring down-regulation of ErbB2.
P78 Palmitoyl chloride 98%  
P9716 Palmitoyl coenzyme A lithium salt ≥90% Long chain fatty acid (C16) covalently linked to Coenzyme A. Covalent attachment of palmitate is a common occurrence on a wide variety of viral and cellular proteins and plays a role in promoting membrane binding. Palmitoylation may also be a general mechanism for prolonging or potentiating G-protein signaling.
Palmitoyl coenzyme A is useful in the biosynthesis of sphingosine, a component of sphingolipids and phospholipids.
SML0869 Phox-l2 ≥98% (HPLC) Phox-I2 is an inhibitor of the NADPH oxidase enzyme complex (NOX2) activation that binds to p67phox and abolishes Rac1 binding. Phox-I2 inhibits NOX2-mediated superoxide production in human and murine neutrophils without detectable toxicity.
SML1295 RBC8 ≥98% (HPLC) RBC8 is a selective inhibitor of the Ras-like GTPases RalA and RalB, downstream mediators of Ras signalling, without direct inihibition of Ras or RhoA activity. RBC8 binds to a site on the GDP-bound form of Ral, its inactive state, inhibiting the binding of Ral to its effectors, such as Ral-binding protein 1 (RALBP1; also known as RLIP760, which are involved in proliferation, survival, and metastasis of several human cancers. RBC8 inhibited growth in human luung cancer cell lines with IC50 values of 2.0 μM in H2122 cells and 1.3 μM in H358 cells, and also inihbited tumor xenograft growth..
SML1166 Salirasib ≥98% (HPLC) Salirasib (Farnesylthiosalicylic acid) is a RAS inhibitor that acts by dislodging the farnesylated protein from the membrane, facilitating Ras degradation. Salirasib impairs downstream signaling and suppresses growth and migration of proliferating tumor cells in in vitro and in vivo models. Salirasib (Farnesylthiosalicylic acid) has recently been shown to possess significant anti-inflammatory and anti-arthritic properties.
Salirasib (S-trans,trans-Farnesylthiosalicylic Acid /FTS) is a synthetic small molecule that has an ability to block all forms of Ras, unlike farnesyltransferase inhibitors, which fail to inhibit K-Ras and N-Ras function due to alternative membrane-binding mechanisms. Salirasib along with gemcitabine, exhibits anti-tumor activity and biomarker modulation in preclinical models of metastatic pancreatic adenocarcinoma (PDA). It is also used as a potent therapeutic for lung cancer.
SML1668 Tipifarnib ≥98% (HPLC) Tipifarnib (R115777) is an orally active and potent farnesyltransferase (FTase) inhibitor that exhibits potent anti-tumorigenic effects. Tipifarnib mechanism of action is not fully understand.