Deltarasin

KRAS-PDEδ interaction inhibitor CAS# 1440898-61-2

Deltarasin

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Chemical structure

Deltarasin

3D structure

Chemical Properties of Deltarasin

Cas No. 1440898-61-2 SDF Download SDF
PubChem ID 73292904 Appearance Powder
Formula C40H37N5O M.Wt 603.75
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : ≥ 42 mg/mL (69.57 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 1-benzyl-2-[4-[(2S)-2-(2-phenylbenzimidazol-1-yl)-2-piperidin-4-ylethoxy]phenyl]benzimidazole
SMILES C1CNCCC1C(COC2=CC=C(C=C2)C3=NC4=CC=CC=C4N3CC5=CC=CC=C5)N6C7=CC=CC=C7N=C6C8=CC=CC=C8
Standard InChIKey LTZKEDSUXKTTTC-KXQOOQHDSA-N
Standard InChI InChI=1S/C40H37N5O/c1-3-11-29(12-4-1)27-44-36-17-9-7-15-34(36)42-39(44)32-19-21-33(22-20-32)46-28-38(30-23-25-41-26-24-30)45-37-18-10-8-16-35(37)43-40(45)31-13-5-2-6-14-31/h1-22,30,38,41H,23-28H2/t38-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Deltarasin

DescriptionDeltarasin is an inhibitor of KRAS-PDEδ interaction with Kd of 38 nM for binding to purified PDEδ.In Vitro:In liver cells, deltarasin inhibits the interaction of RAS with PDEδ with Kd of 41 nM. Inhibition of PDEδ-KRAS interaction by deltarasin suppresses proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS[1].In Vivo:Deltarasin (10 mg/kg, i.p.) impairs dose-dependent tumor growth in nude mice bearing subcutaneous human Panc-Tu-I tumour cell xenografts[1].

References:
[1]. Zimmermann G, et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature. 2013 May 30;497(7451):638-42. [2]. Agalioti T, et al. Mutant KRAS promotes malignant pleural effusion formation. Nat Commun. 2017 May 16;8:15205. doi: 10.1038/ncomms15205.

Protocol

Kinase Assay [1]
Kd values are measured by fluorescence polarization measurements. For direct titrations, increasing amounts of PDEδ are added to a solution containing 50-100 nM labelled small molecule in 200 µL PBS buffer. For displacement titrations, increasing amounts of the small molecules in DMSO are directly added to fluorescein-labelled atorvastatin (24 nM) and His6-tagged PDEδ (40 nM) in 200 µL PBS-buffer (containing 0.05% CHAPS, 1% DMSO), keeping the concentration of fluorescein-labelled atorvastatin, PDEδ and DMSO constant. For Kd measurements using isothermal titration calorimetry, PDEδ protein (280 µM) is titrated to small molecule (30 µM) in Tris/HCl buffer (temperature 25°C). In the Tm shift assays, protein melting points are detected by circular dichroism spectroscopy in the presence of small molecules.

References:
[1]. Zimmermann G, et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature. 2013 May 30;497(7451):638-42. [2]. Agalioti T, et al. Mutant KRAS promotes malignant pleural effusion formation. Nat Commun. 2017 May 16;8:15205. doi: 10.1038/ncomms15205.

Deltarasin Dilution Calculator

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Preparing Stock Solutions of Deltarasin

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.6563 mL 8.2816 mL 16.5631 mL 33.1263 mL 41.4079 mL
5 mM 0.3313 mL 1.6563 mL 3.3126 mL 6.6253 mL 8.2816 mL
10 mM 0.1656 mL 0.8282 mL 1.6563 mL 3.3126 mL 4.1408 mL
50 mM 0.0331 mL 0.1656 mL 0.3313 mL 0.6625 mL 0.8282 mL
100 mM 0.0166 mL 0.0828 mL 0.1656 mL 0.3313 mL 0.4141 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Deltarasin

The KRAS oncogene product is considered a major target in anticancer drug discovery. Interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Deltarasin is an inhibitor of the KRAS-PDEδ interaction to impair oncogenic KRAS signalling.

In vitro: Within a minute, 5 mM of deltarasin completely inhibited PDEδ-KRAS interaction and released the insolubilized mCitrine-RHEB/KRAS6Q to the endomembrane system. This showed that deltarasin interfered with the binding of KRAS to PDEδ in cells and thereby inhibited its solubilization [1].

In vivo: A clear dose-dependent reduction in Panc-Tu-I tumour growth rate could be observed in deltarasin treated mice with respect to the vehicle-injected controls, where the growth of tumours in mice that were treated with 10mg kg/1 BID deltarasin was almost completely blocked [1].

Clinical trial: No clinical data are available.

Reference:
[1] Zimmermann G, Papke B, Ismail S, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PI, Waldmann H.  Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature. 2013;497(7451):638-42.

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References on Deltarasin

Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity.[Pubmed:29440631]

Cell Death Dis. 2018 Feb 13;9(2):216.

Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEdelta interactions by binding to a hydrophobic pocket on PDEdelta, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of Deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that Deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEdelta and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances Deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated Deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of Deltarasin can be enhanced by simultaneously blocking "tumor protective" autophagy, but inhibited if combined with an anti-oxidant.

Plasma membrane phosphatidylinositol 4-phosphate and 4,5-bisphosphate determine the distribution and function of K-Ras4B but not H-Ras proteins.[Pubmed:28939768]

J Biol Chem. 2017 Nov 17;292(46):18862-18877.

Plasma membrane (PM) localization of Ras proteins is crucial for transmitting signals upon mitogen stimulation. Post-translational lipid modification of Ras proteins plays an important role in their recruitment to the PM. Electrostatic interactions between negatively charged PM phospholipids and basic amino acids found in K-Ras4B (K-Ras) but not in H-Ras are important for permanent K-Ras localization to the PM. Here, we investigated how acute depletion of negatively charged PM polyphosphoinositides (PPIns) from the PM alters the intracellular distribution and activity of K- and H-Ras proteins. PPIns depletion from the PM was achieved either by agonist-induced activation of phospholipase C beta or with a rapamycin-inducible system in which various phosphatidylinositol phosphatases were recruited to the PM. Redistribution of the two Ras proteins was monitored with confocal microscopy or with a recently developed bioluminescence resonance energy transfer-based approach involving fusion of the Ras C-terminal targeting sequences or the entire Ras proteins to Venus fluorescent protein. We found that PM PPIns depletion caused rapid translocation of K-Ras but not H-Ras from the PM to the Golgi. PM depletion of either phosphatidylinositol 4-phosphate (PtdIns4P) or PtdIns(4,5)P2 but not PtdIns(3,4,5)P3 was sufficient to evoke K-Ras translocation. This effect was diminished by Deltarasin, an inhibitor of the Ras-phosphodiesterase interaction, or by simultaneous depletion of the Golgi PtdIns4P. The PPIns depletion decreased incorporation of [(3)H]leucine in K-Ras-expressing cells, suggesting that Golgi-localized K-Ras is not as signaling-competent as its PM-bound form. We conclude that PPIns in the PM are important regulators of K-Ras-mediated signals.

Mutant KRAS promotes malignant pleural effusion formation.[Pubmed:28508873]

Nat Commun. 2017 May 16;8:15205.

Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor Deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.

Identification of pyrazolopyridazinones as PDEdelta inhibitors.[Pubmed:27094677]

Nat Commun. 2016 Apr 20;7:11360.

The prenyl-binding protein PDEdelta is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEdelta, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEdelta with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEdelta inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEdelta knockdown in a set of human pancreatic cancer cell lines.

Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase.[Pubmed:29618512]

J Biol Chem. 2018 May 18;293(20):7659-7673.

Rap1 proteins are members of the Ras subfamily of small GTPases involved in many biological responses, including adhesion, cell proliferation, and differentiation. Like all small GTPases, they work as molecular allosteric units that are active in signaling only when associated with the proper membrane compartment. Prenylation, occurring in the cytosol, is an enzymatic posttranslational event that anchors small GTPases at the membrane, and prenyl-binding proteins are needed to mask the cytoplasm-exposed lipid during transit to the target membrane. However, several of these proteins still await discovery. In this study, we report that cyclase-associated protein 1 (CAP1) binds Rap1. We found that this binding is GTP-independent, does not involve Rap1's effector domain, and is fully contained in its C-terminal hypervariable region (HVR). Furthermore, Rap1 prenylation was required for high-affinity interactions with CAP1 in a geranylgeranyl-specific manner. The prenyl binding specifically involved CAP1's C-terminal hydrophobic beta-sheet domain. We present a combination of experimental and computational approaches, yielding a model whereby the high-affinity binding between Rap1 and CAP1 involves electrostatic and nonpolar side-chain interactions between Rap1's HVR residues, lipid, and CAP1 beta-sheet domain. The binding was stabilized by the lipid insertion into the beta-solenoid whose interior was occupied by nonpolar side chains. This model was reminiscent of the recently solved structure of the PDEdelta-K-Ras complex; accordingly, disruptors of this complex, e.g. Deltarasin, blocked the Rap1-CAP1 interaction. These findings indicate that CAP1 is a geranylgeranyl-binding partner of Rap1.

Description

Deltarasin is an inhibitor of KRAS-PDEδ interaction with Kd of 38 nM for binding to purified PDEδ.

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