C. H. Arrowsmith

CACHE Challenge #1: targeting the WDR domain of LRRK2, a Parkinson's Disease associated protein.

The paper evaluates computational hit-finding methods for targeting the WDR domain of LRRK2, a Parkinson's disease protein, finding that diverse strategies yielded weakly potent compounds.

A resource to enable chemical biology and drug discovery of WDR Proteins

The paper develops a resource for discovering ligands for WDR proteins using experimental and computational methods, leading to the identification of drug-like ligands for 9 out of 20 targets.

Huntingtin is an RNA-binding protein and participates in NEAT1-mediated paraspeckles

This study identifies huntingtin as an RNA-binding protein that interacts with G-rich RNA sequences, including those in the NEAT1 paraspeckle lncRNA.

EHMT2/G9a-Inhibition Reprograms Cancer-Associated Fibroblasts (CAFs) to a More Differentiated, Less Proliferative and Invasive State

This study identifies EHMT2 as a key regulator of CAF hyperproliferation and pro-invasive behavior, showing its inhibition reprograms CAFs to a less aggressive state.

PRMT1 is a critical dependency in clear cell renal cell carcinoma through its role in post-transcriptional regulation of DNA damage response genes

Discovery and characterization of a chemical probe targeting the zinc-finger ubiquitin-binding domain of HDAC6

The paper identifies and characterizes a chemical probe, SGC-UBD253, that targets the HDAC6 UBD with selectivity, and a less active derivative as a negative control.

Expanding the Huntingtons disease research toolbox; validated huntingtin subdomain constructs for biochemical and structural investigation of the huntingtin protein

This paper develops validated HTT subdomain constructs for biochemical and structural studies of huntingtin protein interactions and function.

A combinatorial anticancer drug screen identifies off-target effects of epigenetic chemical probes

This study identifies epigenetic chemical probes that enhance TAK-243 cytotoxicity via off-target ABCG2 inhibition and develops a cell-based assay to measure ABCG2 inhibition.

PRMT5 regulates ATF4 transcript splicing and oxidative stress response

This study shows PRMT5 regulates ATF4 splicing and oxidative stress response in AML, with EVI1-high cells depending on PRMT5 for redox balance.

Discovery of small molecule antagonists of human Retinoblastoma Binding Protein 4 (RBBP4)

This study identifies small molecule antagonists of RBBP4's top pocket, competes with protein and histone interactions, and reports the first crystal structure of RBBP4 with a small molecule.

De Novo Design of Immunoglobulin-like Domains

This paper introduces design rules for immunoglobulin-like domains and demonstrates the de novo creation of stable, functional scaffolds with improved biophysical properties.

The PNUTS-PAD domain recruits MYC to the PNUTS:PP1 phosphatase complex via the oncogenic MYC-MB0 region

This paper identifies the MB0 region of MYC as a direct binder to the PNUTS amino-terminal domain (PAD), revealing a molecular mechanism for MYC regulation by the PNUTS:PP1 phosphatase complex.

Structure, activity and inhibition of human TMPRSS2, a protease implicated in SARS-CoV-2 activation

This study characterizes the structure and function of TMPRSS2, a protease involved in SARS-CoV-2 activation, and identifies features for developing selective inhibitors.

HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon 1

This study reveals how HAP40 orchestrates HTT structure, affecting its interaction with polyglutamine-expanded exon 1, providing insights into Huntington's disease mechanisms.

Pharmacological targeting of a PWWP domain demonstrates cooperative control of NSD2 localization

The paper develops a chemical probe, UNC6934, that targets the PWWP1 domain of NSD2, revealing cooperative control of NSD2 localization through chromatin reader domains.

A First-in-class, Highly Selective and Cell-active AllostericInhibitor of Protein Arginine Methyltransferase 6 (PRMT6)

This paper reports the discovery of a first-in-class, highly selective allosteric inhibitor of PRMT6, SGC6870, with potent activity and selectivity in vitro and in cells.

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

This study identifies small-molecule antagonists of the NSD2 PWWP domain that block its interaction with H3K36me2, providing a tool for further investigation of NSD2's role in disease.

Identification of Lysine Isobutyrylation as A New Histone Modification Mark

The paper identifies lysine isobutyrylation as a new histone modification mark and shows its role in epigenetic regulation and cellular physiology.

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

This study shows that GLUT1 inhibition reduces growth of RB1-positive TNBC cells with high glycolytic activity and low OXPHOS, suggesting a therapeutic target in this subset.

Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

The paper identifies small molecule antagonists targeting the USP5 ZnF-UBD, providing a framework for developing chemical probes to study its role in ubiquitin signaling.

A Chemical Probe of CARM1 Alters Epigenetic Plasticity against Breast Cancer Cell Invasion

This study identifies SKI-73 as a CARM1 chemical probe that reduces breast cancer cell invasion by altering epigenetic plasticity, distinct from CARM1 knockout effects.

Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response

This study identifies a PRMT7 inhibitor and shows its effect on arginine methylation of stress proteins, linking PRMT7 to cellular stress response.

Structural basis of HMCES interactions with DNA reveals multivalent substrate recognition

This study reports crystal structures of the HMCES SRAP domain bound to DNA-damage substrates, revealing how HMCES recognizes and binds different DNA structures for crosslinking.

A Chemical Toolbox for the Study of Bromodomains and Epigenetic Signaling

The paper presents a set of 25 chemical probes targeting human bromodomains and demonstrates their utility in studying muscle cell differentiation and triple negative breast cancer.