DrugTech Research Community Seminar

Welcome to a webinar organized by the multi-disciplinary research community Drug Discovery and Delivery (DrugTech) at the University of Eastern Finland.

PhD Christopher Asquith, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, USA, will give a talk on Rediscovering the Kinome: Development of a Selective GAK Probe.

Welcome and concluding remarks by Chairman, Professor Antti Poso, School of Pharmacy, University of Eastern Finland. No registration required. 

Exploring the understudied kinome affords a wealth of opportunities. When analysing the literature, common themes emerge. An example of this is the 4-anilinoquinoline scaffold, which while originally designed as an EGFR inhibitor, was also found to be both a potent and narrow-spectrum inhibitor of the cyclin G associated kinase (GAK). GAK is an important regulator of viral and bacterial entry into host cells; so we embarked on an optimization of the 4-anilino group and the 6,7-quinoline substituents. The early result of this effort was to produce a series of GAK inhibitors with nanomolar activity and over 50000-fold selectivity relative to other members of the numb-associated kinase (NAK) subfamily. This then progressed to the development of SGC-GAK-1, a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally related negative control SGC-GAK-1N. This chemical probe set can now be used to interrogate GAK cellular biology and explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases. I will give a brief whistle stop tour of the medicinal chemistry program and highlight some of the translational tools employed on this project.

References:

1. Asquith CRM,* Tizzard GJ, Bennett JM, Wells CI, Elkins JM, Willson TM, Poso A, Laitinen T. Targeting the Water Network in Cyclin G-Associated Kinase (GAK) with 4-Anilino-quin(az)oline Inhibitors. ChemMedChem. 2020, 15, 1200. doi: 10.1002/cmdc.202000150. PMID: 32358915.

2. Asquith CRM,* Laitinen T, Bennett JM, Wells CI, Elkins JM, Zuercher WJ, Tizzard GJ, Poso A. Design and Analysis of the 4-Anilinoquin(az)oline Kinase Inhibition Profiles of GAK/SLK/STK10 Using Quantitative Structure-Activity Relationships. ChemMedChem. 2020, 15, 26. doi: 10.1002/cmdc.201900521. PMID: 31675459.

3. Asquith CRM,* Bennett JM, Su L, Laitinen T, Elkins JM, Pickett JE, Wells CI, Li Z, Willson TM, Zuercher WJ.* Towards the Development of an In vivo Chemical Probe for Cyclin G Associated Kinase (GAK). Molecules. 2019, 24, 4016. doi: 10.3390/molecules24224016. PMID: 31698822.

4. Asquith CRM,* Treiber DK, Zuercher WJ.* Utilizing comprehensive and mini-kinome panels to optimize the selectivity of quinoline inhibitors for cyclin G associated kinase (GAK). Bioorg Med Chem Lett. 2019, 29, 1727. doi: 10.1016/j.bmcl.2019.05.025. PMID: 31129055.

5. Asquith CRM, Berger BT, Wan J, Bennett JM, Capuzzi SJ, Crona DJ, Drewry DH, East MP, Elkins JM, Fedorov O, Godoi PH, Hunter DM, Knapp S, Müller S, Torrice CD, Wells CI, Earp HS, Willson TM, Zuercher WJ.* SGC-GAK-1: A Chemical Probe for Cyclin G Associated Kinase (GAK). J Med Chem. 2019, 62, 2830. doi: 10.1021/acs.jmedchem.8b01213. PMID: 30768268.

6. Asquith CRM, Laitinen T, Bennett JM, Godoi PH, East MP, Tizzard GJ, Graves LM, Johnson GL, Dornsife RE, Wells CI, Elkins JM, Willson TM, Zuercher WJ.* Identification and Optimization of 4-Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase. ChemMedChem. 2018, 13, 48. doi: 10.1002/cmdc.201700663. PMID: 29072804.