Lewis Elson
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View article: Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2
Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2 Open
Developing new E3 ligase ligands for the design of heterobivalent molecules, such as PROteolysis TArgeting Chimeras (PROTACs), requires careful evaluation of target engagement (TE). Characterizing protein-protein interactions (PPIs) is the…
View article: Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK)
Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK) Open
STK10 (serine/threonine kinase 10, LOK), is an important regulator of diverse cellular processes, such as cell cycle progression and lymphocyte migration. STK10 has emerged as a potential therapeutic target for diseases associated with imp…
View article: Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2
Overcoming Ligand Discovery Challenges: Developing Peptide-Based Tracers for SPSB2 Open
Developing new E3 ligase ligands for the design of heterobivalent molecules, such as PROteolysis TArgeting Chimeras (PROTACs), requires careful evaluation of target engagement (TE). Characterizing protein-protein interactions (PPIs) is the…
View article: Un-LOK-ing a new approach for conformational selective targeting of STK10 (LOK)
Un-LOK-ing a new approach for conformational selective targeting of STK10 (LOK) Open
STK10 (serine/threonine kinase 10, LOK), is an important regulator of diverse cellular processes, such as cell cycle progression or lymphocyte migration. STK10 has emerged as a potential therapeutic target for diseases associated with impa…
View article: Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor
Covalent Targeting Leads to the Development of a LIMK1 Isoform-Selective Inhibitor Open
Selectivity for closely related isoforms of protein kinases is a major challenge in the design of drugs and chemical probes. Covalent targeting of unique cysteines is a potential strategy to achieve selectivity for highly conserved binding…
View article: Type II kinase inhibitors that target Parkinson’s disease–associated LRRK2
Type II kinase inhibitors that target Parkinson’s disease–associated LRRK2 Open
Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson’s disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowl…
View article: Covalent targeting leads to the development of LIMK1 isoform-selective inhibitors
Covalent targeting leads to the development of LIMK1 isoform-selective inhibitors Open
Selectivity for closely related isoforms of protein kinases is a major challenge in the design of drugs and chemical probes. Covalent targeting of unique cysteines is a potential strategy to achieve selectivity for highly conserved binding…
View article: Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor
Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor Open
Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds to an allosteric pocket created by an αC-out/DFG-out conformation. This inactive conformation results in a large expansion…
View article: Workflow for E3 Ligase Ligand Validation for PROTAC Development
Workflow for E3 Ligase Ligand Validation for PROTAC Development Open
Proteolysis targeting chimeras (PROTACs) have gained considerable attention as a new modality in drug discovery. The development of PROTACs has been mainly focused on using CRBN (Cereblon) and VHL (Von Hippel-Lindau ligase) E3 ligase ligan…
View article: Chemogenomics for steroid hormone receptors (NR3)
Chemogenomics for steroid hormone receptors (NR3) Open
The nine human NR3 nuclear receptors translate steroid hormone signals in transcriptomic responses and operate multiple highly important processes ranging from development over reproductive tissue function to inflammatory and metabolic hom…
View article: Repurposing of the RIPK1 selective benzo[1,4]oxazepin-4-one scaffold for the development of a type-III LIMK1/2 inhibitor
Repurposing of the RIPK1 selective benzo[1,4]oxazepin-4-one scaffold for the development of a type-III LIMK1/2 inhibitor Open
Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds as a type-III inhibitor targeting the αC-out/DFG-out conformation. This inactive conformation results in a large expansion…
View article: Type-II kinase inhibitors that target Parkinson’s Disease-associated LRRK2
Type-II kinase inhibitors that target Parkinson’s Disease-associated LRRK2 Open
Aberrant increases in kinase activity of leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s disease (PD). Numerous LRRK2-selective type-I kinase inhibitors have been developed and some have entered clinical trials. In thi…
View article: Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors
Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors Open
Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family.…
View article: Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting
Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting Open
Casein kinase-2 (CK2) are serine/threonine kinases with dual co-factor (ATP and GTP) specificity, that are involved in the regulation of a wide variety of cellular functions. Small molecules targeting CK2 have been described in the literat…
View article: Chemogenomics for NR1 nuclear hormone receptors
Chemogenomics for NR1 nuclear hormone receptors Open
Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are relevant as drug targets, the NR1 family, which comprises 19 NRs bindin…
View article: Functional characterization of pathway inhibitors for the ubiquitin-proteasome system (UPS) as tool compounds for CRBN and VHL-mediated targeted protein degradation
Functional characterization of pathway inhibitors for the ubiquitin-proteasome system (UPS) as tool compounds for CRBN and VHL-mediated targeted protein degradation Open
Summary Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) or molecular glues are new modalities for drug development and important tools for target validation. Both modalities recruit an E3 ubiquitin ligase to a pro…
View article: Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting
Synthesis and evaluation of chemical linchpins for highly selective CK2α targeting Open
Casein kinase-2 (CK2) are serine/threonine kinases with dual co-factor (ATP and GTP) specificity, that are involved in the regulation of a wide variety of cellular functions. Small molecules targeting CK2 have been described in the literat…
View article: Development of Selective Pyrido[2,3- <i>d</i> ]pyrimidin-7(8 <i>H</i> )-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors
Development of Selective Pyrido[2,3- <i>d</i> ]pyrimidin-7(8 <i>H</i> )-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors Open
Mammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less c…
View article: Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity
Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity Open
Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of …
View article: Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3
Synthesis of Pyrazole-Based Macrocycles Leads to a Highly Selective Inhibitor for MST3 Open
MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20-like serine/threonine (MST) family that regulate cellular functions such as proliferation and migration. The MST3 isozyme plays a role in regulating cell gr…
View article: Development of selective pyrido[2,3-<i>d</i>]pyrimidin-7(8<i>H</i>)-one-based Mammalian STE20-like (MST3/4) kinase inhibitors
Development of selective pyrido[2,3-<i>d</i>]pyrimidin-7(8<i>H</i>)-one-based Mammalian STE20-like (MST3/4) kinase inhibitors Open
Mammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and autophagy pathways, and their dysregulation has been implicated in cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less c…
View article: Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3
Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3 Open
MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20 kinase (MST) family. MSTs regulate key cellular functions such as cell proliferation, cell migration, metabolic regulation, and cell polarity. The MST3 isoz…
View article: Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8<i>H</i>)-one inhibitors towards the salt-inducible kinase (SIK) subfamily
Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8<i>H</i>)-one inhibitors towards the salt-inducible kinase (SIK) subfamily Open
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 ova…
View article: Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family
Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family Open
The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases of the dark kinome. They exhibit a highly conserved binding pocket and are activated by cyclin Y binding. CDK16 is ta…