| Reference | 1. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6495-9. doi: 10.1016/j.bmcl.2011.08.070.
Epub 2011 Aug 22. <br />
<br />
Inhibition of c-Kit, VEGFR-2 (KDR), and ABCG2 by analogues of OSI-930. <br />
<br />
Patel JP(1), Kuang YH, Chen ZS, Korlipara VL. <br />
Author information: <br />
(1)Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health
Professions, St. John/’s University, Queens, NY 11439, USA. <br />
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 10μM and 1μM, respectively and 88% and
50% inhibition of KDR at 10μM and 1μM, 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 13.67μM and 16.67μM, respectively. <br />
<br />
2. Cancer Res. 2006 Jan 15;66(2):1015-24. <br />
<br />
OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor
tyrosine kinases with antitumor activity in mouse xenograft models. <br />
<br />
Garton AJ(1), 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. <br />
Author information: <br />
(1)OSI Pharmaceuticals Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
[email protected] <br />
OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase
insert domain receptor (KDR), which is currently being evaluated in clinical
studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact
cells and also inhibits these targets in vivo following oral dosing. We have
investigated the relationships between the potency observed in cell-based assays
in vitro, the plasma exposure levels achieved following oral dosing, the time
course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor
xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged
inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this
dose range was associated with antitumor activity. Similarly, prolonged
inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral
doses of 100 to 200 mg/kg, which was the dose level associated with significant
antitumor activity in this model as well as in the majority of other xenograft
models tested. The data suggest that antitumor activity of OSI-930 in mouse
xenograft models is observed at dose levels that maintain a significant level of
inhibition of the molecular targets of OSI-930 for a prolonged period.
Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930
at these effective dose levels provides an estimate of the target plasma
concentrations that may be required to achieve prolonged inhibition of Kit and
KDR in humans and which would therefore be expected to yield a therapeutic
benefit in future clinical evaluations of OSI-930. <br />
<br />
3. Mol Cancer Ther. 2005 Aug;4(8):1186-97. <br />
<br />
Temporal quantitation of mutant Kit tyrosine kinase signaling attenuated by a
novel thiophene kinase inhibitor OSI-930. <br />
<br />
Petti F(1), Thelemann A, Kahler J, McCormack S, Castaldo L, Hunt T, Nuwaysir L,
Zeiske L, Haack H, Sullivan L, Garton A, Haley JD. <br />
Author information: <br />
(1)OSI Pharmaceuticals, Inc., 1 Bioscience Park Drive, Farmingdale, NY 11735,
USA. <br />
OSI-930, a potent thiophene inhibitor of the Kit, KDR, and platelet-derived
growth factor receptor tyrosine kinases, was used to selectively inhibit tyrosine
phosphorylation downstream of juxtamembrane mutant Kit in the mast cell leukemia
line HMC-1. Inhibition of Kit kinase activity resulted in a rapid
dephosphorylation of Kit and inhibition of the downstream signaling pathways.
Attenuation of Ras-Raf-Erk (phospho-Erk, phospho-p38), phosphatidyl inositol-3/’
kinase (phospho-p85, phospho-Akt, phospho-S6), and signal transducers and
activators of transcription signaling pathways (phospho-STAT3/5/6) were measured
by affinity liquid chromatography tandem mass spectrometry, by immunoblot, and by
tissue microarrays of fixed cell pellets. To more globally define additional
components of Kit signaling temporally altered by kinase inhibition, a novel
multiplex quantitative isobaric peptide labeling approach was used. This approach
allowed clustering of proteins by temporal expression patterns. Kit kinase, which
dephosphorylates rapidly upon kinase inhibition, was shown to regulate both Shp-1
and BDP-1 tyrosine phosphatases and the phosphatase-interacting protein PSTPIP2.
Interactions with SH2 domain adapters [growth factor receptor binding protein 2
(Grb2), Cbl, Slp-76] and SH3 domain adapters (HS1, cortactin, CD2BP3) were
attenuated by inhibition of Kit kinase activity. Functional crosstalk between Kit
and the non-receptor tyrosine kinases Fes/Fps, Fer, Btk, and Syk was observed.
Inhibition of Kit modulated phosphorylation-dependent interactions with pathways
controlling focal adhesion (paxillin, leupaxin, p130CAS, FAK1, the Src family
kinase Lyn, Wasp, Fhl-3, G25K, Ack-1, Nap1, SH3P12/ponsin) and septin-actin
complexes (NEDD5, cdc11, actin). The combined use of isobaric protein
quantitation and expression clustering, immunoblot, and tissue microarray
strategies allowed temporal measurement signaling pathways modulated by mutant
Kit inhibition in a model of mast cell leukemia. <br />
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