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  • Journal article

  • Structure-based design of selective salt-inducible kinase (SIK) inhibitors

    • Authors : Tesch, Roberta (2021)

  • Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences i...
  • Journal Article

  • Drug repurposing approach for potential Pfmrk inhibitors as antimalarial agents: an In-silico analysis

    • Authors : McBride, John M. (2023)

  • Alteration of one or few amino acid residues can affect structure [1–3] and function [4] of a protein and, in extreme cases, be the difference between health and disease [5, 6]. Understanding structural consequences of point mutations is important for drug design [7, 8] and could also accelerate optimization of enzymatic function via directed evolution [9, 10]. In these and other applications, theoretical models [11] could...
  • Journal Article

  • Drug repurposing approach for potential Pfmrk inhibitors as antimalarial agents: an In-silico analysis

    • Authors : Sahu, Abhishek (2023)

  • Malaria is a major global health issue due to the emergence of resistance to most of the available antimalarial drugs. There is an urgent need to discover new antimalarials to tackle the resistance issue. A CDK- like protein, Pfmrk from Plasmodium falciparum, plays a crucial role in regulating cell proliferation and shares 36.28% homology with humans CDK (hCDK7). Pfmrk complex with Pfcyc-1 and stimulates kinase activity. Also, Pfcyc-1 from P.&#...
  • Journal Article

  • Fluorogenic Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide Activated SIRT7

    • Authors : Bolding, Julie E. (2023)

  • The sirtuins are NAD+-dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biology, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ε-N-acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms; in part, because of a...
  • Journal article

  • Computationally Guided Design of Novel Angiotensin Converting Enzyme Inhibitors

    • Authors : Lam, Jennifer D. (2023)

  • Angiotensin-converting enzyme inhibitors (ACEI) such as Moexipril, Trandolapril, Ramipril, and Perindopril are used to treat hypertension. However, these drugs have undesired side effects. Using computational studies, two new novel drug candidates were designed with improved molecular interactions, ADMET properties, and docking scores compared to Moexipril. Homology analysis was done to determine the best animal model for preclinical studies, and it revealed that Pan troglo...
  • Industry article

  • Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily

    • Authors : Rak, Marcel (2023)

  • Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicity in vivo, w...
  • Journal article

  • A Recombinant Approach For Stapled Peptide Discovery Yields Inhibitors of the RAD51 Recombinase

    • Authors : Pantelejevs, Teodors (2023)

  • Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinylheteroaryl chemistry, as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeatderived ...