Pyrazolo[3,4-d]pyrimidines as potent inhibitors of the insulin-like growth factor receptor (IGF-IR)

doi:10.1016/j.bmcl.2007.07.037

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 19, 1 October 2007, Pages 5406-5409

https://doi.org/10.1016/j.bmcl.2007.07.037 Get rights and content

Abstract

A high throughput screen of Abbott’s compound repository revealed that the pyrazolo[3,4-d]pyrimidine class of kinase inhibitors possessed moderate potency for IGF-IR, a promising target for cancer chemotherapy. The synthesis and subsequent optimization of this class of compounds led to the discovery of 14, a compound that possesses in vivo IGF-IR inhibitory activity.

Graphical abstract

The synthesis, in vitro and in vivo characterization of a novel class of insulin-like growth factor receptor tyrosine kinase inhibitors, the pyrazolo[3,4-d]pyrimidines, is disclosed.

References and notes (18)

E.A. Bohula et al.
Anti-Cancer Drugs
(2003)
R.D. Hubbard et al.
Chem Med Chem.
(2007)
Arnold, L. D.; Cesario, C.; Coate, H.; Crew. A. P.; Dong, H.; Foreman, K.; Honda, A.; Laufer, R.; Li, A.-H.; Mulvihill,...
Wishart, N.; Friedman, M.; Arnold, L. D.; Yang, B.; Fix-Stenzel, S. R.; Ericsson, A.; Michaelides, M. R.; Qian, X.-D.;...
A. Arora et al.
J. Pharmacol. Exp. Ther.
(2005)
R. Tibes et al.
Annu. Rev. Pharmacol. Toxicol.
(2005)
D. Yee
Br. J. Cancer
(2006)
B.S. Miller et al.
Cancer Res.
(2005)
E. Foulstone et al.
J. Pathol.
(2005)
G. Romano
Drug News Perspect.
(2003)

There are more references available in the full text version of this article.

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Citation Excerpt :
Figure 32 represents the SAR of compounds and their potency toward IGFIR, EGFR and ErbB2 as well as effect on receptor phosphorylation. Hubbard et al.100 synthesized and also investigated the potential of pyrazolo[3,4-d]pyrimidines to inhibit the insulin-like growth factor receptor (IGF-IR). They assessed the compounds with significant potency for cellular and enzymatic activity (Fig. 33).
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Pyrazolo[3,4-d]pyrimidines as potent inhibitors of the insulin-like growth factor receptor (IGF-IR)

Abstract

Graphical abstract

Anti-Cancer Drugs

Chem Med Chem.

J. Pharmacol. Exp. Ther.

Annu. Rev. Pharmacol. Toxicol.

Br. J. Cancer

Cancer Res.

J. Pathol.

Drug News Perspect.