As a result, our current research efforts have been directed towards the Hippo-pathway and the integrated stress response or ISR pathway that cancers exploit and become highly dependent on, compared with healthy cells. Two areas particular interest within our group where this emerging approach has been successful in identifying novel chemical entities (NCEs) targeting kinases that regulate transcription are the NUAK/MARKs inhibitors as Hippo-pathway modulators and GCN2 inhibition in the Integrated Stress Response (ISR) pathway inhibitors.

The Hippo signaling pathway relies on the transcriptional activity of yes associated protein (YAP) and its cofactor TEAD. The YAP-TEAD complex via target gene expression gets associated with the development, proliferation, and progression of cancerous cells. YAP adorns cancer cells with several oncogenic traits such as inhibition of apoptosis, enhanced proliferation, drug resistance, and immune response suppression. Therefore, inhibition of the YAP activity is an appealing and viable therapeutic strategy for cancer treatment. However, developing small molecule drug-like inhibitors of YAP/TAZ is challenging due to several factors, such as the unstructured nature of transcription factors and targeting a protein-protein interaction. Through a collaboration with Dr. Liliana Attisano using a cellular functional screen, we discovered NUAKs (NUAK1 and NUAK2) a poorly studied class of AMPK family kinases, as a cancer-relevant negative regulator of the Hippo pathway (Nat Commun. 2018; 9:3510). Moreover, we identified a novel scaffold with lead compounds demonstrating excellent kinase potency and selectivity with good cellular YAP inhibition profile which is currently being optimized for oral efficacy. More importantly, there is also a Hippo-pathway-YAP signature profile that allows the meticulous selection of tumours that will likely respond to treatment.

GCN2 (the kinase protein encoded by EIF2AK4) represents one arm of the ISR pathway, whereby cells adapt to various stresses such as amino acid deprivation (Proc. Natl. Acad. Sci. USA 2018;115(33): E7776-E7785, Science 2020, 368: eaat5314). Activation of the ISR pathway, in turn, promotes cellular adaptation to overcome these stress conditions. Thus, activation of the ISR-GCN2-ATF4 pathway represents a stress response pathway and protective mechanism employed by a subset of malignant cells (e.g., ovarian, and multiple myeloma cells). In collaboration with Dr. Robert Rottapel, we screened our kinase library at GCN2 and subjected the hits to a scaffold melding and hybridization process using a new GCN2 model developed by our experienced computational and modeling team. This effort successfully led to two novel series of GCN2 inhibitors currently in lead optimization (Science 2020, 368: eaat5314). Another important translational aspect to this approach is the identification of key ISR-GCN2 pathway signatures and potential biomarkers as predictors of sensitivity to small molecule inhibitor treatment (Science 2020, 368: eaat5314).

The development of potent and selective kinase inhibitors as agents to modulate the Hippo pathway and the intrinsic stress response (ISR) as potential therapeutics for ovarian cancer have contributed to the development of a rich pipeline of projects that are currently being pursued.