Neovastat Ae941 structure unknown

Neovastat is a naturally occurring orally bioavailable antiangiogenic compound, extracted from shark cartilage, under investigation by AEterna Zen-taris (Quebec, Canada). Neovastat possesses multiple antiangiogenic mechanisms of action that provide broad therapeutic potential for a number of diseases 294,295 . The development of Neovastat first began due to the mistaken belief that sharks, whose skeletons consist mostly of cartilage, are not affected by cancer. Despite the fact that this...

Semaxanib SU5416 SU6668 and Sunitinib SU11248

Semaxanib (SU5416), an antiangiogenic agent developed by SUGEN (Ownership of SUGEN passed to Pfizer www.pfizer.com as part of its acquisition of Pharmacia in April 2003), was one of the most advanced agents in clinical development. Semaxanib is a KDR TK antagonist that exhibits inhibitory activities against PDGFR, Flt1 and Flt4 as well 21,215 . Biochemical studies indicated that Semaxanib possesses ATP mimetic properties, and exerts its inhibitory effects on the signaling pathway of KDR Flk1 in...

PI3KPKB Pathway Modulators with Unknown Mechanism of Action

Effective PI3K PKB pathway interruption has also been reported with a series of compounds whose mechanism of action is still unknown. The three examples reviewed in this section also illustrate the potential application and challenges that chemical genetics may face in this area of drug discovery. Triciribine, also known as Akt protein kinase B signaling inhibitor-2 (API-2) compound 52, Fig. 9), was identified by screening the National Cancer Institute Diversity Set chemical library (1992...

Pharmacology of 5aReductase Inhibitors

Finasteride, the first 5a-reductase inhibitor, was introduced more than a decade ago. It competitively inhibits 5aR-2 but is only weakly active against type 1. It reduces human serum DHT levels by 65-70 and prostatic DHT levels by 85-90 130 . The efficacy, safety and ability to reverse the natural progression of benign prostatic hyperplasia have convincingly been demonstrated. Since serum testosterone levels are unaffected, side effects such as decreased libido, fertility and sexual function...

XL647 and XL999 structure unavailable

XL647 EXEL-647 and XL999 are two potent spectrum selective inhibitors under development by Exelixis South San Francisco, CA, www.exelixis.com . These compounds aim at targeting both the tumor and its vasculature by inhibiting different RTKs implicated in driving tumor proliferation and vas-cularization 213,290,310,311 . XL647 simultaneously inhibits the EGFR, HER2, KDR, and EphB4 TK with high potency and demonstrates excellent activity in target-specific cellular functional assays....

Src Kinase Inhibitor Drug Development for Cancer Therapy

Following the milestone discovery of Src kinase about 30 years ago, there has been extraordinary progress in advancing structural, biochemical, cellular, and in vivo studies of Src kinase towards delineating its role s in both normal physiology and pathophysiological states, including cancer and bone disease. Src kinase has been established to be functionally involved in cellular proliferation, survival, and migration. Such activities provide an opportunity to leverage strategies for drug...

Pyridopyrimidinone Template Based Inhibitors PD180970 PD173955 and PD166326

PD180970 5 , PD173955 6 , and PD166326 7 89-98 have been determined to be potent inhibitors of Src and Abl kinase with varying selectivities to PDGFR, FGFR, EGFR, and Kit kinases. PD173955 effects potent antiproliferative activity in cancer cell lines e.g., MDA-MB-468 breast cancer cells , and it exemplifies a novel class of antimotic inhibitors involving Src and Yes kinases, which have roles in cellular progression through the initial phase of mitosis. PD180970 is a highly potent inhibitor of...

Purine Template Based Inhibitors AP23464 AP23848 AP23846 AP23994 AP23451 and AP23588

AP23464 13 , AP23848 14 , AP23846 15 , AP23994 16 , AP23451 17 , and AP23588 18 7,24,32,37,38,69,116-129 are highly potent inhibitors of Src kinase IC50 or Ki range 1-10 nM . AP23464 has been utilized to examine the functional relationship of Src and FAK in adhesion turnover associated with migration of colon cancer cells and to provide mechanistic proof-of-concept correlating Src tyrosine kinase as a key therapeutic target. Specifically, Src kinase-dependent phosphorylation of FAK at Tyr-925...

AP23464 and AP23848

ARIAD has published extensively on non-ATP competitive Src kinase inhibitors as potential agents for the treatment of osteoporosis 101 . These efforts were later expanded to ATP competitive Src kinase inhibitors that were based on a purine template. These compounds were designed to target bone via the incorporation of a bisphosphonate group 102 . AP23464 20 , which contains a dimethylphosphine oxide substituent, inhibited Src with an IC50 of 0.45 nM and inhibited Abl with an IC50 of 0.67 nM...