Human tumors possess both genetic and cellular heterogeneity which conspire to limit the therapeutic effectiveness of targeted therapy. These fundamental elements of tumor biology require combination therapy, as demonstrated in other therapeutic settings such as HIV, to create long term disease control and therapeutic effectiveness. Two prevailing challenges in oncology drug discovery are the identification of the most effective drug combinations and the design of multiple inhibitory activities into a single compound. Kinases are well known regulatory enzymes that drive key aspects of tumor cell signaling and uncontrolled growth and survival. This family of enzymes share sequence homologies enabling the combination of activities into a single molecule. However, it remains unclear which inhibitory activities and how to de novo design such a molecule. The Celgene chemical library, which is rich in kinase inhibitory scaffolds, was screened using a NSCLC derived cell line under tumor-stimulated growth stress using low glucose and low serum growth conditions and in the presence of the Celgene TORKi CC-223. The therapeutic hypothesis built into this phenotypic screen centers on identifying kinase inhibitors with unique selectivity profiles that will convert the growth inhibitory effect of mTOR pathway inhibition into an apoptotic effect.   Scaffolds that induced an apoptotic effect only in the presence of CC-223 were selected for follow-up. This cell-based screen and subsequent SAR studies produced a series of unique potent and selective ERK/NLK kinase inhibitors, with single agent activity, targeting three important tumor cell proliferation / survival pathways: MAPK, Wnt, and Hippo.  Compounds in this series demonstrate potent antiproliferative activity in vitro and activity in both cell line xenograft and patient derived tumor in vivo models.  Synthesis, structure activity optimization, in vitro and in vivo efficacy data will be reported.

Identification and optimization of a series of novel kinase inhibitors targeting three important tumor cell proliferation / survival pathways: MAPK, Wnt, and hippo

ACS Spring 2022

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