Patent Watch

May 14, 2013

These compounds may add to the cancer drug arsenal. I. Aliagas-Martin and co-inventors disclose compounds represented by formula 1 that inhibit serine–threonine protein kinase PAK1. The compounds may be useful for treating hyperproliferative and neoplastic diseases.

Protein kinases catalyze the phosphorylation of hydroxyl groups in specific tyrosine, serine, or threonine residues in proteins. This process can be essential for regulating a wide variety of cell processes such as metabolism, proliferation, and differentiation. Interrupting any of these cell processes can result in diseases such as cancer and diabetes.

Protein kinases fall into two main groups: protein tyrosine kinases (PTKs) and serine–threonine kinases (STKs). Both can be receptor or nonreceptor protein kinases. The p21-activated protein kinases (PAKs) are a family of nonreceptor STKs that play important roles in cytoskeletal organization, cellular morphogenesis, cellular processes, and cell survival.

General structure and representative examples of STK PAK1 inhibitors.

The six members of the PAK family are subdivided into two groups. Group I contains PAKs 1–3, and group II contains PAKs 4–6. PAKs are important mediators of Rac and Cdc42 GTPase functioning and the pathways required for Ras-driven tumorigenesis.

The PAK family members are important signaling molecules that are frequently overexpressed in cancerous tissues. Many human malignancies are associated with aberrant levels and overactivities of PAKs in general and PAK1 in particular. Compounds that inhibit or modulate the activity and signal-transduction pathways of overactive or overexpressed STKs, particularly PAK1, may be useful for treating hyperproliferative and neoplastic diseases.

Biological activity was measured by the GST-PAK1-KD inhibition assay and MEK1 (S298) phosphorylation assay.

Four representative examples of formula 1 are shown in the figure. Their biological activity was measured by the GST-PAK1-KD inhibition assay and MEK1 (S298) phosphorylation assay and is shown in the table.

(F. Hoffmann-La Roche [Basel, Switzerland]. WIPO Publication 2013026914, Feb. 28, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

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