X-396 Potent, Selective ALK Inhibitor

Anaplastic lymphoma kinase (ALK) was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies now indicate that in addition to ALCL, abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer and neuroblastomas, a childhood cancer. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising target for molecularly targeted cancer therapy.

The anaplastic lymphoma kinase (ALK) is deregulated by multiple mechanisms including translocation to form a constitutively active fusion protein, activating mutations in the kinase, and gene amplification. The EML4-ALK fusion protein is found in a subpopulation of non-smokers that develop NSCLC.  Multiple fusion proteins other than EML4-ALK have been identified in patients with ALCL (anaplastic large cell lymphoma). Similarly, multiple activating mutations in the kinase domain have been found in children with neuroblastoma.

Xcovery has developed X-396 for treatment of these diseases and others where ALK is deregulated. X-396 has been validated in potency and selectivity assays indicating that it is more selective and up to 10 times more potent than competitive ALK inhibitors.  X-396 has been active in animal models of NSCLC and neuroblastoma. Importantly X-396 has shown activity in ALK mutations that confer resistance to other small molecule ALK inhibitors. These data in conjunction with preliminary toxicology and pharmacokinetic data suggest that X-396 should be an effective, well tolerated oral treatment for ALK positive NSCLC, Lymphoma, and neuroblastoma.

Xcovery will be initiating a Phase I clinical trial in the beginning of 2012.

Recent Publications:

Insights into ALK-Driven Cancers Revealed through Development of Novel ALK Tyrosine Kinase Inhibitors.
Lovly CM, Heuckmann JM, de Stanchina E, Chen H, Thomas RK, Liang C, Pao W.
Cancer Res. 2011 Jul 15;71(14):4920-4931. Epub 2011 May 25.