CMLD-2

Inhibitor of ELAVL1

Structure

Information

  • ELAVL1
  • Inhibitor

In Vitro Validations

Uniprot ID: Q15717
Target Class: Other
Target SubClass: RNA Binding Protein
Potency: Ki
Potency Value: 0.35 uM
Potency Assay: FP assay, AlphaLISA assay, SPR
PDB ID for probe-target interaction (3D structure): --
Target aliases:
ELAV-like protein 1, HUR, ELAVL1, ELAV1_HUMAN, HuR ...

In Cell Validations

In Vivo Data

No in Vivo Validations

I have extra information to add

SERP ratings and comments


SERP Ratings

In Cell Rating

SERP Comments:

CMLD-2 is a compound that emerged from a limited size HTS conducted to identify disruptors of binding between HuR protein (also known as ELAVL1) and mRNA  adenine- and uridine-rich elements (ARE). The screening assay appears to have been appropriately validated and optimized as a part of the original publication (Wu et al., 2015).

  • MAJOR ISSUE: lack of selectivity data. CMLD-2 (PubChem CID: 16746438) was identified as a hit in other screening campaigns for other targets (for example as a  Mcl-1/Noxa Interaction Inhibitor, and in other contexts). I don’t take this to mean conclusively that this compound is promiscuous but additional tests are needed to establish the full scope of targets. Additionally, it is not clear that the observed phenotype is HuR dependent, and more work needs to be done to establish that the observed phenotype is driven by CMLD-2 mediated disruption of HuR/ARE interaction. The lack of selectivity information precludes endorsement of CMLD-2 as a chemical probe (tool compound) for study of HuR (ELAVL1). 

MINOR POINTS FOR CMLD-1 DEVELOPERS TO CONSIDER

  • The reported binding between HuR and ARE is on the order of low nM. The measured Ki of the lead screening hit CMLD-2 was 350nM. The hit compound was used without further optimization. I would advise a structure-guided med chem campaign to improve the in vitro binding while testing for in cell activity and target engagement at this point.
  • No SAR analysis. The HTS yielded a class of related compounds as hits but it is not clear whether any SAR trends can be rationalized.
  • The proposed negative control compound NC-3 retained some binding (2 uM) under same conditions. In cell viability assays in HCT-116, CMLD-2 IC50 was around 30 uM vs. 70 uM for NC-3. Similar was seen in MiaPaCa2 cells. Although other data did suggest that NC-3 is a much weaker inhibitor of HuR/ARE interaction, it is not a inactive, and therefore this calls into question whether NC-3 can be used as a negative control. I would advise caution here, and additional work on developing a better negative control compound. One might emerge from SAR work suggested above.

(last updated: 26 Jul 2020 )

SERP Ratings

In Cell Rating

SERP Comments:

The molecule is chiral and lacks an enantiomeric comparison. Care using this probe must be taken as chromone template is known to interfere with spectrometric assays. The compound is reported as active in other RNA and DNA dependant assays in Pubchem Database.

(last updated: 28 Aug 2020 )