AMG 176

Antagonist of MCL1

Structure

Information

  • MCL1
  • Antagonist
  • 1 nM

In Vitro Validations

Uniprot ID: Q07820
Target Class: Other
Target SubClass: BCL2 family
Potency: Ki
Potency Value: 60 pM
Potency Assay: Time-resolved fluorescence resonance energy transfer binding assays
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: yes
Target aliases:
Induced myeloid leukemia cell differentiation prot ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): TR-FRET
Probe Selectivity in Vitro:

Selective with BCL-xL 0.7 uM And BCL2 0.95 uM

I have extra information to add

SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

 

Targeting hMCL-1 by a small molecule is a challenge. The interaction of hMCL-1 and AMG 176 has been characterised (PDB: 6OVC) and this should be added to the review form.

No information regarding the selectivity of AMG 176 outside the primary target is provided and this is a large gap in its biological properties. AMG 176 is a direct antagonist of MCL-1 but classified as an “apoptosis regulator” and this process involves many targets. Therefore, the AMG 176 selectivity profile outside the target family (e.g. kinase) needs to be included in the review form. This is of relevance to compounds developed for oncology as they often exhibit poly-pharmacology.

Further details of the assays (TR-FRET binding assay and HEK293M cellular) should be provided. The cellular assay appears to make use of AM-8621 which is a close analogue of AMG 761 and these findings may not translate to AMG 176.

AMG 176 is a complex molecule with potentially reactive groups and will have a relatively high cost for synthesis/purchase. It is therefore not clear whether its bio-activity is due to the parent molecule or metabolite/s. The results of appropriate stability studies should be included in the review form.

The physico-chemical properties of AMG 176 are not reported. The solubility (solvent and concentration), potential reactivities and QC (NMR, mass spec, mp, etc), storage recommendations and stability (dry powder and solution) and sensitivities (e.g. freeze/thaw cycles) should be provided in the review form.

With a 60 pM Ki, recommending the use of 1µM AMG 176 in a cellular assay is excessive (currently ~17,000x Ki).

A pubchem search for AMG 176 (https://pubchem.ncbi.nlm.nih.gov/compound/118910268#section=Names-and-Identifiers) reveals that its molecular weight (613.2 g/mol) is relatively high and when taken together with a high tPSA (93.3 Ų), makes it undesirable for oral delivery, although this route is mentioned in the review form. AMG 176 would also not be CNS penetrant (Pajouhesh and Lenz, Medicinal Chemical Properties of Successful Central Nervous System Drugs, NeuroRx. 2005 Oct; 2(4): 541–553. doi: 10.1602/neurorx.2.4.541).

 

(last updated: 27 Oct 2020 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

A very close analogue (AM-8621) was tested in several cell lines, and demonstrate activity in AML cell lines, therefore I decided to classify this probe as ‘good to use in cells’. DOI: 10.1158/2159-8290.CD-18-0387

(last updated: 4 Nov 2020 )