A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion

Abstract

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 (6a in this work) is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 (6a) can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for several days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 (6a) recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73(6a)-associated reduction of invasiveness acts by altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 (6a) and CARM1 knockout alter the epigenetic plasticity with remarkable difference, suggesting distinct modes of action for small-molecule and genetic perturbations. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

Probing the SAM Binding Site of SARS-CoV-2 Nsp14 In Vitro Using SAM Competitive Inhibitors Guides Developing Selective Bisubstrate Inhibitors

“…Keeping this substitution in designing future nsp14 inhibitors will provide selectivity against PKMTs. WZ16 42 and compound 8 are PRMT4 (CARM1) inhibitors. Although compound 8 is a relatively weak nsp14 inhibitor (IC 50 = 95 ± 6 µM), it is likely cell permeable (US20180305391A1).…”

Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4)

“…This degree of selectivity provides a promising framework for the development of higher potency chemical probes for cellular assays. Interestingly, nine structures have recently been added to the PDB of CARM1 from Mus musculus in complex with different aromatic-containing bisubstrate inhibitors (PDB codes 5TBJ, 5TBI, 5TBH, 5LV3, 5LV2 [36] and 5ISB 5IS9, 6DVR and 6D2L [38]). Superposition of these structures with the CARM1-9 complex structure (Supplementary Figure S9) revealed reasonably good overlap of 9's aminopyridine group with the aromatic groups of these inhibitors, particularly in the SAM carboxylate binding pocket (i.e.…”

“…Design of selective inhibitors is challenging however, since the residues involved in SAM and substrate arginine binding are largely conserved in the nine PRMTs encoded in the human genome, particularly between type I family members [37]. In line with recent advances [38], the development and structural investigation of rationally designed bisubstrate inhibitors remains a desirable route to identify individual residue variations that may contribute to selective inhibition of CARM1 over PRMT1 for example. (B) Structures of bisubstrate azo-SAM inhibitors from the present study (4-10) and those reported previously by van Haren et al [28,33].…”

Single cell RNA sequencing for breast cancer: present and future

“…They found that small subclones of breast cancer cells expressing IL11 and vascular endothelial growth factor D (VEGFD) synergistically promoted metastasis, among which scRNA-seq of CD45+ cell populations from primary tumors, blood, and lungs showed that IL11 acts on bone marrow-derived mesenchymal stromal cells and induces pretumorigenic and premetastatic neutrophils to promote the progression of tumor metastasis 36 . In addition, Cai et al 37 proposed the chemical probe arginine methyltransferase CARM1 to combat the invasion of breast cancer cells by changing epigenetic plasticity using scRNA-seq. The study revealed that high heterogeneity caused by genetic and epigenetic characteristics of cancer subsets serves as a mechanism to promote tumor metastasis.…”