SU9516: biochemical analysis of cdk inhibition and crystal structure in complex with cdk2

Moshinsky, Deborah; Bellamacina, Cornelia; Boisvert, D.C.; Huang, Ping; Hui, Terence; Jancarik, J.; Kim, Sung‐Hou; Rice, Audie

doi:10.1016/j.bbrc.2003.09.114

Cited by 46 publications

(41 citation statements)

References 30 publications

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“…The C3 substituent points towards the outside of the pocket. The same binding has been observed for other compounds of the same class (Mohammadi et al 1997, Moshinsky et al 2003. This result suggests that our model of RET kinase domain is reliable.…”

Section: Molecular Modelingsupporting

confidence: 85%

Inhibition of RET tyrosine kinase by SU5416

Mologni

Sala

Cazzaniga

et al. 2006

Journal of Molecular Endocrinology

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Thyroid neoplasia is frequently associated with rearranged during transfection (RET) proto-oncogene mutations that cause hyperactivation of RET kinase activity. Selective inhibition of RET-mediated signaling should lead to an efficacious therapy. SU5416 is a potent inhibitor of vascular endothelial cell growth factor receptor, c-Kit, and FLT-3 receptor tyrosine kinases presently used in clinical trials. We found that SU5416 inhibits RET with similar potency, both in cell-free assays and in cells, thus causing proliferation arrest in oncogenic RET-transfected cells and in papillary thyroid carcinoma (PTC) cells expressing the RET/PTC1 oncogene, but not in RET-negative control cells. SU5416 inhibited RET-mediated signaling through the extracellular signal regulated kinase (ERK) and JNK pathways. In addition, we show that a naturally occurring MEN2 mutation at codon 804 confers resistance to SU5416, but not to the related compound SU4984. We provide a possible explanation to these results by using molecular docking. Finally, SU5416 was also assessed against an array of 52 tyrosine and serine/threonine kinases.

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Section: Molecular Modelingsupporting

confidence: 85%

Inhibition of RET tyrosine kinase by SU5416

Mologni

Sala

Cazzaniga

et al. 2006

Journal of Molecular Endocrinology

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“…The apparent divergence in mechanism of inhibition between HER1 and HER2 is not without precedent. A small-molecule inhibitor of the cyclin-dependent kinases was previously shown to inhibit cyclin-dependent kinase 2 and cyclin-dependent kinase 4 by distinct mechanisms (39). Similarly, an inhibitor of the Src kinase families was found to exhibit distinct modes of inhibition of two highly related members within the family (40).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling

Wong¹,

Lee²,

Yu³

et al. 2006

Clinical Cancer Research

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Purpose: The studies described here are intended to characterize the ability of BMS-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1and/or HER2. Experimental Design: The potency and selectivity of BMS-599626 were assessed in biochemical assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was determined in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunoprecipitation. Antitumor activity of BMS-599626 was evaluated using a number of different xenograft models that represent a spectrum of human tumors with HER1or HER2 overexpression. Results: BMS-599626 inhibited HER1and HER2 with IC 50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC 50 in the range of 0.24 to 1 Amol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity. Conclusions: BMS-599626 is a highly selective and potent inhibitor of HER1and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an additional mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth.The preclinical data support the advancement of BMS-599626 into clinical development for the treatment of cancer.

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“…Structural investigations demonstrated that the higher potency of these two variants is due to formation of additional interactions with the polar residue Asp86, while the "standard" triplet of hydrogen bonds is retained [17,30]. A puzzling exception is 3-(3H-Imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516) which appears to form only the standard hydrogen bond triplet but is highly potent and also presents a good degree of selectivity for CDK2 against CDK4 [31,32]. Unlike potency, the issue of selectivity has proven to be much harder to explain via analysis of the available crystal structures only [11,12].…”

Section: Introductionmentioning

confidence: 99%

Novel Structural Features of CDK Inhibition Revealed by an ab Initio Computational Method Combined with Dynamic Simulations

et al. 2006

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The rational development of specific inhibitors for the ∼500 protein kinases encoded in the human genome is impeded by poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects -so far undetected by crystallography-affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP-binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK-inhibitor interactions, and explain the unexpectedly high potency of certain inhibitors like 3-(3H-Imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures, and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors.2

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SU9516: biochemical analysis of cdk inhibition and crystal structure in complex with cdk2

Cited by 46 publications

References 30 publications

Inhibition of RET tyrosine kinase by SU5416

Inhibition of RET tyrosine kinase by SU5416

Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling

Novel Structural Features of CDK Inhibition Revealed by an ab Initio Computational Method Combined with Dynamic Simulations

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