The emergence of resistance mechanisms to existing kinase-targeting drugs has motivated a search for alternative approaches of shifting the focus from oncogene inhibition to the inhibition of basal cellular processes.
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) and MARKs (more specifically MARK3), 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.
- Principal Scientist and Drug Discovery Group Leader, Ontario Institute for Cancer Research
- President and Founder, Climb Consulting
- Director of Medicinal Chemistry, Cascade Therapeutics Inc
- Director of Medicinal Chemistry, Bioquest Innovations Inc
- Drug Discovery Group Leader, NPS Pharmaceuticals
- Senior Scientist, Scientist IV, NPS Pharmaceuticals
- Research Scientist Scientist III, NPS Pharmaceuticals
- Research Scientist Scientist II, NPS Pharmaceuticals
- Research Scientist, Scientist I, Allelix Biopharmaceutical Inc.
- Senior Scientific Advisor and Group Leader, Drug Discovery Program, OICR
- Member of the American Association for Cancer Research (AACR)
- Scientific and Project Leader for the Open Science Initiative to develop ALK2 inhibitors for DIPG, M4K Pharma
- Edilova, Maria I.; Law, Jaclyn C.; Zangiabadi, Safoura; Ting, Kenneth; Mbanwi, Achire N.; Arruda, Andrea; Uehling, David; Isaac, Methvin; Prakesch, Michael; Al-awar, Rima; Minden, Mark D.; Abdul-Sater, Ali A.; Watts, Tania H. The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia OncoImmunology 2021, 10(1), 1943234/1.
- Uehling, David E.; Joseph, Babu; Chung, Kim Chan; Zhang, Andrew X.; Ler, Spencer; Prakesch, Michael A.; Poda, Gennady; Grouleff, Julie; Aman, Ahmed; Kiyota, Taira; Leung-Hagesteijn, Chungyee; Konda, John David; Marcellus, Richard; Griffin, Carly; Subramaniam, Ratheesh; Abibi, Ayome; Strathdee, Craig A.; Isaac, Methvin B.; Al-awar, Rima; Tiedemann, Rodger E. Design, Synthesis and Characterization of 4-Aminoquinazolines as Potent Inhibitors of the G Protein-Coupled Receptor Kinase 6 (GRK6) for the Treatment of Multiple Myeloma Journal of Medicinal Chemistry 2021, 64(15), 11129-11147.
- Murrell, Emily; Tong, Junchao; Smil, David; Kiyota, Taira; Aman, Ahmed M.; Isaac, Methvin B.; Watson, Iain D. G.; Vasdev, Neil Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors ACS Medicinal Chemistry Letters 2021, 12(5), 846-850.
- Smil, David; Wong, Jong Fu; Williams, Eleanor P.; Adamson, Roslin J.; Howarth, Alison; McLeod, David A.; Mamai, Ahmed; Kim, Soyoung; Wilson, Brian J.; Kiyota, Taira; Aman, Ahmed; Owen, Julie; Poda, Gennady; Horiuchi, Kurumi Y.; Kuznetsova, Ekaterina; Ma, Haiching; Hamblin, J. Nicole; Cramp, Sue; Roberts, Owen G.; Edwards, Aled M.; Uehling, David; Al-awar, Rima; Bullock, Alex N.; O’Meara, Jeff A.; Isaac, Methvin B. Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma, Journal of Medicinal Chemistry 2020, 63(17), 10061-10085.
- Ensan, Deeba; Smil, David; Zepeda-Velazquez, Carlos A.; Panagopoulos, Dimitrios; Wong, Jong Fu; Williams, Eleanor P.; Adamson, Roslin; Bullock, Alex N.; Kiyota, Taira; Aman, Ahmed; Roberts, Owen G.; Edwards, Aled M.; O’Meara, Jeff A.; Isaac, Methvin B.; Al-Awar, Rima. Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma Journal of Medicinal Chemistry 2020, 63(9), 4978-4996.
- CTIP Incubator Award for the Open Science ALK2 Discovery Project
- CTIP Late Accelerator Award for MARK3 Inhibitors as Hippo-pathway modulators for Cancer
- CTIP Late Accelerator Award for GCN2 Inhibitors as ISR modulators for Ovarian Cancer
- CIHR Award: The Discovery and Optimization of NUAK Inhibitors: A Novel Approach to Target Hippo Pathway Driven Cancers
We are open to local (the Ontario research ccommunity), provincial and international collaboration, especially in the areas of drugging oncology targets where research interests are aligned.