Richard D. Connell

Discovery and Pharmacologic Characterization of CP-724,714, a Selective ErbB2 Tyrosine Kinase Inhibitor

Amplification and overexpression of erbB2 (Her-2/neu) proto-oncogene has been linked to human malignancies including tumors of the breast, ovary, and stomach. It has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients, and disease-free survival. Although the clinical use of trastuzumab (Herceptin) has prolonged the survival of breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent and orally bioavailable small-molecule inhibitors. CP-724,714 is a potent inhibitor of erbB2 receptor autophosphorylation in intact cells and is currently undergoing phase I clinical trials. Here, we describe the effects of CP-724,714 in vitro and in vivo in human breast cancer models. CP-724,714 is selective for inhibiting growth of HER2-driven cell lines. In addition, we show that it induces G1 cell cycle block in erbB2-overexpressing BT-474 human breast carcinoma cells and inhibits erbB2 autophosphorylation in xenografts when administered p.o. to athymic mice. It induces a marked reduction of extracellular signal-regulated kinase and Akt phosphorylation, tumor cell apoptosis, and release of caspase-3. P.o. administration (q.d. or b.i.d.) of CP-724,714 inhibits the growth of erbB2-overexpressing tumors in athymic mice without overt adverse effects.

Patent focus on cancer chemotherapeutics V. Angiogenesis agents: September 2001 – August 2002

Angiogenesis refers to the formation of new capillaries from existing blood vessels and is believed to be a key process in tumour growth. Angiogenesis inhibition represents an active area of cancer drug discovery, with several agents and approaches now entering late stage clinical development. This review summarises the key aspects of recent patent applications relating to cancer chemotherapy and drug discovery that involve inhibition or modulation of angiogenesis. The review includes applications that have been published between September 2001 and August 2002. In particular, the review focuses on the approaches aimed at growth factor targets, such as angiopoietin, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF).

Cancer chemotherapeutics - angiogenesis agents: October 1999 - March 2000

Angiogenesis is often defined as the formation of capillary blood vessels from existing blood vessels. In the area of cancer research, approaches that seek to block angiogenesis are under intense investigation. In the past six months, a number of applications have appeared referring to small molecule inhibitors of matrix metalloproteinases (MMPs), the VEGF receptor tyrosine kinase, the integrin receptor αvβ3 and other defined targets. This review summarises the key features of these applications as well as other disclosures involving natural products claimed as angiogenesis inhibitors. The review also summarises angiogenesis-related disclosures involving endogenous inhibitors, novel targets and interesting technologies that have appeared in applications published between October 1999 and March 2000. If the patent activity is any indication, there is significant interest and a number of opportunities for treating cancer through inhibiting angiogenesis.

The 2-oxindole chemotype and patent activity inspired by the SU5416 franchise

Indol-2-ones or 2-oxoindole-based tyrosine kinase inhibitors (TKIs) were originally identified in the late 1980s by researchers in Japan and Italy. Interest in this series of TKIs increased significantly following the disclosure of SU5416, a clinical candidate from Sugen for the treatment of cancer. During the clinical development of SU5416, there was a significant increase in patent filings related to TKIs containing 2-oxindole groups, both inside and outside of Sugen. This review will look at the patent activity inspired by the 2-oxoindole kinase inhibitors from the late 1980s to applications published through April of 2003.

Discovery and synthesis of novel 4-aminopyrrolopyrimidine Tie-2 kinase inhibitors for the treatment of solid tumors.

The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.

Patent focus on cancer chemotherapeutics. II Angiogenesis agents: April 2000 - September 2000

Angiogenesis refers to the formation of capillary blood vessels from existing blood vessels: a process that is believed to be critical for tumour growth and metastasis. Angiogenesis inhibition represents a new approach to cancer chemotherapy with several agents and approaches now entering late clinical development. This review summarises the key aspects of recent patent applications referring to inhibitors of angiogenesis that have been published between April and September 2000. The review covers the main mechanism-based approaches such as MMPI, integrin antagonists, urokinase inhibitors and inhibitors of the growth factor signalling pathways of fibroblast growth factor (FGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and Tie-2/Tek. Applications referring to endogenous inhibitors such as endostatin or angiostatin are also included, as are selected natural products that have data suggesting a link to angiogenesis-specific mechanisms of action.

Patent focus on cancer chemotherapeutics. III Angiogenesis agents: October 2000 – March 2001

Angiogenesis refers to the formation of new blood vessels from existing blood vessels, a process that is believed to be a key requirement for tumour growth and metastasis. Angiogenesis inhibition represents a new approach to cancer chemotherapy and several agents and approaches are now entering late clinical development. This review summarises the key aspects of recent patent applications referring to cancer chemotherapy and cancer drug discovery that involve inhibition or reduction of angiogenesis. The review covers the main mechanism-based approaches such as MMPIs, inhibitors of the growth factor signalling pathways, integrin antagonists and urokinase inhibitors. Additional sections relating to vascular damaging agents, endogenous inhibitors and selected natural products are also included. The scope includes applications that published from October 2000 through March 2001.