SU5416 (Semaxanib) (Figure 4) is a synthetic small molecule inhibitor of the tyrosine kinase domain of VEGFR-2. SU5416 is also a potent competitive inhibitor of KIT and less potently the PDGFR (indirectly involved in angiogenesis), but is not directly cytotoxic by itself. Recent work has also suggested that SU5416 may medi-

ate some of its effects through inhibition of a second VEGFR [8]. Preclinical xenograft models have confirmed inhibition of tumor growth and a reduction in the number of metastases following treatment with SU5416, as well as a decrease in vascular density in treated tumors as measured by intravital video-microscopy. SU5416 recently underwent phase II clinical trials for its safety and efficacy in patients with recurrent or metastatic head and neck cancer [9].

Karsten et al. [10] disclosed the expression of VEGFR-1/2 and its ligand VEGF in AML cell lines and characterized the inhibitory action of the protein TKI SU5614 (Figure 5) (5-Chloro-3-[(3,5-dimethylpyrrol-2-yl)methylene]-2indolinone) on human endothelial and leukemic cells. The results of this study showed intracellular VEGF expression was detected in 9 of 10 leukemic cell lines. In contrast, VEGFR-1 and VEGFR-2 expression was restricted to 6 and 2 out of 10 cell lines, respectively. Although SU5614 was a effective inhibitor of the VEGFinduced endothelial cell sprouting in vitro, the sensitivity of leukemic cells toward the growth inhibitory activity of the compound was determined by the c-kit, but not by the VEGFR-1/2 expression. SU5614 induced growth arrest and apoptosis in c-kit expressing Kasumi-1, UT-7, and M-07e cells and inhibited the stem cell factor induced tyrosine phosphorylation of c-kit.

SU6668 (Figure 6) is a selective inhibitor of the recaptors for VEGFR, PDGFRβ and FGFR1 [11]. SU6668 inhibits the growth of tumor cell lines in vitro and has significant anti-tumor activity in xenografts after daily oral treatment. Laird and co-workers [12] determined the kinase inhibitory profile of SU6668, which is a more water soluble 2-oxindole derivative than SU5416. Using steady state enzyme kinetics with purified recombinant VEGFR-2, they reported that this compound is a competitive inhibitor with respect to ATP.

SU14813 (Figure 7), an orally active indolinone multitargeted TKIs, blocks VEGFR-1, -2, and -3, PDGFR-α, -β, c-kit, and FLT3 at nanomolar concentrations [13]. In vitro, SU14813 inhibited VEGFR-2, PDGFRβ, and FLT3 internal tandem duplication phosphorylation, with cellular IC₅₀ values of 0.04, 0.02, and 0.05 µmol/l, respecttively, and showed anti-tumor efficacy in tumor xenograft models. Preclinical studies in mice demonstrated a lack of major active metabolites, linear pharmacokinetics and oral bioavailability of 40%.

Shem et al. [14] reported a encouraging preclinical data for SU14813 and the clinical implications for its use based on a similar potency to Sunitinib but distinct pharmacokinetic profile, which may favorably affect tolerability and allow greater dosing flexibility, SU14813

warrants further clinical evaluation in human malignancies, both alone and in combination with cytotoxic chemotherapy.

SU11274 (Figure 8) is an ATP competitive small molecule inhibitor of the catalytic activity of Met which exhibited selectivity for Met enzyme versus a panel of other tyrosine kinases [15]. Chemically SU11274 is a [(3Z)-N- (3-chlorophenyl)-3-({3,5-dimethyl-4-[(4-methylpiperazin-1-yl)carbonyl]-1H-pyrrol-2-yl} methylene)-N-methyl-2- oxoindoline-5-sulfonamide]. Recent studies demonstrate that SU11274, a prototypic anti-MET small molecule, is an effective inhibitor of both HGF dependent and independent signaling, which results also from the presence of point mutations. Inhibition of the Met kinase activity by SU11274 led to time and dose dependent reduced cell growth and induced G1 cell cycle arrest and apoptosis. The bulk of clinical and experimental evidence has suggested that Met is a potential therapeutic target for development of inhibitors for treatment of cancers. Xueyan et al. [16] reported the identification and characterization of small molecule inhibitors SU11274 that potently and selectively inhibit the enzymatic activity of Met kinase. SU11274 displayed much lower IC₅₀ values for inhibittion of Met, then towards other tyrosine kinases includes EGFR, FGFR1 or Src, thus, suggesting its high speci- ficity. SU11274 belongs to a class of small molecule RTK inhibitors that exert their activity by competing for the Mg-ATP complex binding pocket, which results in inhibition of kinase activity and subsequent downstream signaling.

SU12662 (Figure 9) is an active N-desethyl metabolite of Sunitinib. SU12662 has receptor tyrosine kinase inhibitory profile similar to that of Sunitinib in vitro and has similar plasma protein binding [17].

SU5402 (Figure 10) chemically 3-[(3-(2-carboxyethyl)- 4-methylpyrrol-2-yl) methylene]-2-indolinone shown a selective inhibitory effect of tyrosine kinase with known anti-FGFR activity [18] against control Ba/F3 cells expressing the constitutively active ZNF198-FGFR1 fusion protein, and also against KMS-11 and OPM-2, t(4;14) positive MM cell lines that express activated FGFR3.

Neela et al. [19] reported a novel small molecule inhibitor of VEGFR-2, SU10944 (Figure 11). This indolinone 2- one derivative is an effective, ATP-competitive inhibitor of VEGFR-2 biochemical activity and is active in the nanomolar range in cellular assays. SU10944 can be administered in vivo by the oral route and achieves sufficient exposure to inhibit nearly all VEGF stimulated ne-

ovascularization and vascular permeability. Robert disclosed steady state kinetic analysis of SU10944, he found that this compound is a potent ATP competitive inhibittor of VEGFR-2 in vitro with an IC₅₀ value of 96 nM and a Ki value (a dissociation constant) of 21 nM [20]. They found that SU10944 is a more potent inhibitor of VEGFR- 1 when compared with VEGFR-2. However, the compound is not an effective inhibitor of PDGFRβ, KIT or FGFR1.

SU6656 (Figure 12) is an inhibitor of the Src family of tyrosine kinases [21], a group of enzymes that regulate many important signaling pathways, including RAS/ MAPK, PI3K/AKT and STAT, and which represent molecular targets for the treatment of various cancers. SU6656 showed cross reactivity with certain other kinases such as the Aurora B kinases, proteins that control cell ploidy and centrosome number. SU6656 can also significantly augment the anti-angiogenic effect of irradiation and may be a useful agent in the treatment of drug resistant cancers.

3-substituted indolin-2-ones represent a potent and selec-

tive inhibitor for certain RTKs [22]. These small molecules typically act as adenine mimetics that occupy the ATP binding pocket in specific RTKs, with the specificity being governed by the substituents around the indolinone core. Compounds of this class have reached clinical trials for the treatment of several cancers. One such compound is SU9516 (Figure 13) (3-[1-(3H-Imidazol- 4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2one). From crystal structure of the inhibitor bound to cdk2 and kinetically characterized studies about the inhibition of cdks by SU9516 suggest that this compound could have usefulness as a core molecule for the study of cdk inhibition. Furthermore, information gained from the structural analysis should aid in the development of more potent and specific inhibitors in the future. SU9516 is also reported to inhibit GSK-3 which is involved in normal cell death [23].

SU4984 (Figure 14) chemically 3[4-(1-Formylpiperazin- 4-yl)-benzylidenyl]-2-indolinone derivative inhibits the tyrosine kinase activity of FGFR1 by interacting with the catalytic domain of FGFR1. SU4984 also inhibits FGF-

induced phosphorylation of ERK1 and ERK2 and tyrosine phosphorylation of PDGF and insulin receptors. SU4984 also effective against KIT with juxtamembrane activating mutations [24].