User:Fvasconcellos/CX-4945

Silmitasertib (INN), codenamed CX-4945, is a small-molecule inhibitor of casein kinase II (protein kinase CK2), a constitutively active serine/threonine-specific protein kinase that is overexpressed in several types of tumors.

Silmitasertib is in clinical trials for use as an adjunct to chemotherapy in the treatment of cholangiocarcinoma (bile duct cancer), and in pre-clinical development for other cancers, including hematological and lymphoid malignancies.

In January 2017, it was granted orphan drug status by the U.S. Food and Drug Administration for advanced cholangiocarcinoma. It is being developed by Senhwa Biosciences of Taiwan.

Mechanism of action
Silmitasertib interacts competitively with the ATP-binding site of CK2 subunit alpha. This leads to inhibition of several downstream signaling pathways, including PI3K/Akt.

History
CX-4945 was originated by now-defunct Cylene Pharmaceuticals of San Diego, California, as the culmination of a lengthy process of rational, structure-based molecular modification of a lead compound known to have PARP inhibitor activity. Among a large series of compounds built around a benzo[c]-[2,6]naphthyridine-8-carboxylic acid scaffold, CX-4945 was chosen for its high potency and selectivity as an inhibitor of CK2.

Pre-clinical pharmacokinetics studies conducted in mice, rats, and dogs confirmed that CX-4945 had satisfactory bioavailability when given by mouth and did not block cytochrome P450, while experiments in mice confirmed its inhibition of solid-tumor growth in a dose-dependent manner.

Clinical trials in humans began in 2010, making CK-4945 the first CK2 inhibitor to reach this stage of drug development.