OSI-930

Inhibitor of Kit, KDR, Flt, CSF-1R, c-Raf and Lck CAS# 728033-96-3

OSI-930

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OSI-930

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Chemical Properties of OSI-930

Cas No. 728033-96-3 SDF Download SDF
PubChem ID 9868037 Appearance Powder
Formula C22H16F3N3O2S M.Wt 443.44
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (112.75 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 3-(quinolin-4-ylmethylamino)-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide
SMILES C1=CC=C2C(=C1)C(=CC=N2)CNC3=C(SC=C3)C(=O)NC4=CC=C(C=C4)OC(F)(F)F
Standard InChIKey FGTCROZDHDSNIO-UHFFFAOYSA-N
Standard InChI InChI=1S/C22H16F3N3O2S/c23-22(24,25)30-16-7-5-15(6-8-16)28-21(29)20-19(10-12-31-20)27-13-14-9-11-26-18-4-2-1-3-17(14)18/h1-12,27H,13H2,(H,28,29)
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 OSI-930

DescriptionOSI-930 is a potent inhibitor of receptor tyrosine kinases with IC50 values of 80 nM, 9 nM, 8 nM, 15 nM, 41 nM and 22 nM for c-Kit, KDR, Flt, CSF-1R, c-Raf and Lck , respectively.
Targetsc-KitKDRFltCSF-1Rc-RafLck
IC5080 nM9 nM8 nM15 nM41 nM22 nM

OSI-930 Dilution Calculator

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OSI-930 Molarity Calculator

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Preparing Stock Solutions of OSI-930

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2551 mL 11.2755 mL 22.551 mL 45.1019 mL 56.3774 mL
5 mM 0.451 mL 2.2551 mL 4.5102 mL 9.0204 mL 11.2755 mL
10 mM 0.2255 mL 1.1275 mL 2.2551 mL 4.5102 mL 5.6377 mL
50 mM 0.0451 mL 0.2255 mL 0.451 mL 0.902 mL 1.1275 mL
100 mM 0.0226 mL 0.1128 mL 0.2255 mL 0.451 mL 0.5638 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 OSI-930

OSI-930 is a novel, potent inhibitor of Flt1, kinase insert domain receptor (KDR), CSF-1R, Lck, c-Raf and activated receptor tyrosine kinases Kit with IC50 values of 8, 9, 15, 22, 41 and 80 nM, respectively [1].

OSI-930 has been demonstrated to inhibit proliferation and induce apoptosis in the HMC-1 cell line which is highly dependent on Kit signaling for survival. On the contrary, OSI-930 revealed no growth inhibition of COLO-205 cell line under normal culture conditions [1].

OSI-930 has shown to time- and concentration-dependently inactivate P450 3A4. Additionally, OSI-930 could reduce CO difference spectra of P450 3A4 [2].

References:
[1] Garton AJ1, Crew AP, Franklin M, Cooke AR, Wynne GM, Castaldo L, Kahler J, Winski SL, Franks A, Brown EN, Bittner MA, Keily JF, Briner P, Hidden C, Srebernak MC, Pirrit C, O'Connor M, Chan A, Vulevic B,Henninger D, Hart K, Sennello R, Li AH, Zhang T, Richardson F, Emerson DL, Castelhano AL, Arnold LD,Gibson NW. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res. 2006 Jan 15;66(2):1015-24.
[2] Lin HL1, Zhang H, Medower C, Hollenberg PF, Johnson WW. Inactivation of cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a thiophene-containing anticancer drug. Drug Metab Dispos. 2011 Feb;39(2):345-50.

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References on OSI-930

Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930.[Pubmed:21920748]

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6495-9.

The quinoline domain of OSI-930, a dual inhibitor of receptor tyrosine kinases (RTKs) c-Kit and KDR, was modified in an effort to further understand the SAR of OSI-930, and the binding site characteristics of c-Kit and KDR. A series of 16 compounds with heteroatom substituted pyridyl and phenyl ring systems was synthesized and evaluated against a panel of kinases including c-Kit and KDR. Aminopyridyl derivative 6 was found to be the most active member of the series with 91% and 57% inhibition of c-Kit at 10muM and 1muM, respectively and 88% and 50% inhibition of KDR at 10muM and 1muM, respectively. The target compounds were also tested for their ability to inhibit efflux of mitoxantrone through inhibition of ATP dependent ABCG2 pump. Nitropyridyl derivative 5 and o-nitrophenyl derivative 7 exhibited complete inhibition of the ABCG2 pump with IC(50) values of 13.67muM and 16.67muM, respectively.

OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance.[Pubmed:22750060]

Biochem Pharmacol. 2012 Sep 15;84(6):766-74.

OSI-930, a dual c-Kit and KDR tyrosine kinase inhibitor, is reported to have undergone a Phase I dose escalation study in patients with advanced solid tumors. A series of fifteen pyridyl and phenyl analogues of OSI-930 were designed and synthesized. Extensive screening of these compounds led to the discovery that nitropyridyl and ortho-nitrophenyl analogues, VKJP1 and VKJP3, were effective in reversing ABC subfamily G member 2 (ABCG2) transporter-mediated multidrug resistance (MDR). VKJP1 and VKJP3 significantly sensitized ABCG2-expressing cells to established substrates of ABCG2 including mitoxantrone, SN-38, and doxorubicin in a concentration-dependent manner, but not to the non-ABCG2 substrate cisplatin. However, they were unable to reverse ABCB1- or ABCC1-mediated MDR indicating their selectivity for ABCG2. Western blotting analysis was performed to evaluate ABCG2 expression and it was found that neither VKJP1 nor VKJP3 significantly altered ABCG2 protein expression for up to 72 h. [(3)H]-mitoxantrone accumulation study demonstrated that VKJP1 and VKJP3 increased the intracellular accumulation of [(3)H]-mitoxantrone, a substrate of ABCG2. VKJP1 and VKJP3 also remarkably inhibited the transport of [(3)H]-methotrexate by ABCG2 membrane vesicles. Importantly, both VKJP1 and VKJP3 were efficacious in stimulating the activity of ATPase of ABCG2 and inhibited the photoaffinity labeling of this transporter by its substrate [(125)I]-iodoarylazidoprazosin. The results suggested that VKJP1 and VKJP3, specifically inhibit the function of ABCG2 through direct interaction with its substrate binding site(s). Thus VKJP1 and VKJP3 represent a new class of drugs for reducing MDR in ABCG2 over-expressing tumors.

A phase 1 study of OSI-930 in combination with erlotinib in patients with advanced solid tumours.[Pubmed:23099006]

Eur J Cancer. 2013 Mar;49(4):782-9.

AIM: To determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours. PATIENTS AND METHODS: Eligible patients with advanced solid tumours were enrolled into this standard "three+three" dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed. RESULTS: Twenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID+100 mg erlotinib QD; 200 mg OSI-930 BID+150 mg erlotinib QD; 300 mg OSI-930 BID+150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co-administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d). CONCLUSIONS: 200 mg OSI-930 BID+150 mg erlotinib QD were the recommended doses for further evaluation of this combination.

First-in-human phase I trial of two schedules of OSI-930, a novel multikinase inhibitor, incorporating translational proof-of-mechanism studies.[Pubmed:23403628]

Clin Cancer Res. 2013 Feb 15;19(4):909-19.

PURPOSE: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors. EXPERIMENTAL DESIGN: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted. RESULTS: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n = 8). Dose-limiting toxicities were observed at 600 mg twice a day (n = 3): G3 rash (n = 2) and G4 gamma-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1-2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n = 1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses >/=400 mg, while DCE-MRI responses were shown in 4 of 6 patients. CONCLUSIONS: OSI-930 is safe and well tolerated, with pharmacokinetic-pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity.

Description

OSI-930 is a potent inhibitor of Kit, KDR and CSF-1R with IC50 of 80 nM, 9 nM and 15 nM, respectively; also potent to Flt-1, c-Raf and Lck and low activity against PDGFRα/β, Flt-3 and Abl.

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