S63845

Protein target name:

MCL1

Mechanism of action:

BH3 mimetic Inhibitor

Recommended Concentration for use in cells:

~~Up to 5 uM~~

Reviewer suggested Concentration for use in cells:

up to 1 uM

Probe Availability

MedChem Express

SelleckChem

Probe Information

Target and Probe Information

Target Details

Target class:

Other

Define other target class:

Apotosis regulator

Subclass:

BCL2 family

HUGO ID:

HGNC:6943

Entrez gene ID:

4170

UNIPROT ID:

Q07820

Target alias:

BCL2 family apoptosis regulator, BCL2L3, EAT-ES, MCL1L, MCL1S, Mcl-1, TM, bcl2-L-3, mcl1/EAT, MCL1

Probe Details

Chemical Probes Portal ID:

CPP1534

PubChem CID:

122197581

SMILES string:

Cc1c(-c2c(-c3ccc(F)o3)sc3ncnc(O[C@H](Cc4ccccc4OCc4ccnn4CC(F)(F)F)C(=O)O)c23)ccc(OCCN2CCN(C)CC2)c1Cl

InChi Key:

ZFBHXVOCZBPADE-SSEXGKCCSA-N

Orthogonal probe:

A-1210477AMG 176

Physico-chemical properties

Potential reactivities:

S63845 is sensitive to light.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

MCL1: 0.19 nM

Potency assay:

Surface plasmon resonance assay; in FP assay, S63845 had Ki <1.2 nM for MCL1.

PDB ID for probe-target interaction (3D structure):

5LOF

Off target activity

Potency (off target):

Off target protein and potency:

BCL2 >10,000 nM, BCLXL >10,000 nM

Potency assay (off target):

FP assay

Probe Selectivity in Vitro:

Outside Target Family: S63845 had little activity in BCL2 or BCLXL-dependent H146 cells in apoptosis assays.

In cell validation

On target activity in cells

Potency in cells:

IC50

< 10 nM

Potency assay (cells):

In MCL1-dependent, H929 cells, S63845 had an IC50 <10 nM in apoptosis assays. In HeLa cells, S63845 disrupted MCL1 complex formation with BAX and BAK (co-immunoprecipitation experiments). BAX- and BAK-deficient cells are resistant to S63845.

Target engagement assay (cells):

In HeLa cells, S63845 disrupted MCL1 complex formation with BAX and BAK (co-immunoprecipitation experiments). BAX- and BAK-deficient cells are resistant to S63845.

Off target activity in cells

Potency assay, off target (cells):

S63845 had little activity in BCL2 or BCLXL-dependent H146 cells in apoptosis assays.

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

S63845 is cytotoxic to multiple myeloma cells (IC50<0.1 uM), with the extent of cytotoxicity correlating with BIM2A expression.

In vivo validation

Organism:

SCID and C57BL/6 mice

Dose:

25 mg/kg, Reviewer suggested dose: 6.25-25 mg/Kg IV

Route of delivery:

Intravenous

Organ of Interest

Organ (O):

Xenografts, various

Target engagement assay:

In several xengraft models hematological and solid tumors, S63845 had anti-tumor activity. At the maximum dose (60 mg/kg), S63845 led to marked reduction in erythocytes.

Primary Reference

Reference (doi):

10.1038/nature19830 10.1021/acs.jmedchem.0c01234

Reference (PMID):

27760111 33146521

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

4 review(s)

Rating for use in Model Organisms

4 review(s)

SAB Members

SAB Comments

S63845 is an excellent inhibitor with good potency and selectivity over other BCL2 family members (namely BCL2 and BCL-xL). It is active within mouse in vivo models at reasonable doses with no observable toxicity (note: mouse Mcl1 is significantly different than human MCL1, and many Mcl1 inhibitors do not target the mouse homolog (its not known if S63845 does or does not)). This agent should be considered the current best-in-class agent for targeting MCL1. A modest drawback is the need to utilize a IV route of administration for in vivo studies.

May 1 2017 - 5:25pm

S63845 is a potent and selective MCL-1 inhibitor that is appropriate to use in cellular and in vivo studies. Based on its pharmacokinetic properties, S63845 cannot be dosed orally but requires intravenous dosing instead. Another drawback of this compound is its light sensitivity, which requires extra care in handling. Consistent with findings made for other MCL-1 inhibitors, S63845 has lower affinity to mouse MCL-1 than its human homolog (SPR data: Kd (human MCL-1) = 1.0 nM; Kd (mouse MCL-1) = 5.7 nM). Therefore, the target safety conclusions of the paper reporting this probe (Nature 2016, 538, 477–482), based on the fact that the compound is tolerated in mouse, need to be viewed with caution. Same as other described MCL-1 inhibitors, S63845 is difficult to synthesize and there is currently no robust supply source.

May 17 2017 - 2:59pm

S63845 is a tool compound that was published in 2016 and apparently originated from an optimization program at Servier/WEHI leading to the clinical stage Mcl1 inhibitor S64315. Currently, the published data set for S63845 is broader than for the actual clinical compound. Therefore, it makes sense to use S63845 as a probe compound to study Mcl1 pharmacology. Several alternatives are available with AMG176 and AZD5991, however, all come from the same chemotype and it can therefore not be ruled out that all show related off-targets when used at unnecessarily high concentrations.

Jun 4 2021 - 12:06pm

This probe is also very potent with many other cancer cell line tested, e.g. multiple myeloma derived and lymphoma cell line, as well as some patient, derived samples; No PK/PD relationship showed in the publication and thus somewhat limited its validity for in vivo use. Probe significantly increase MCL1 level in cell. Extremely slow off-rate in SPR data which might affect the accuracy of Kd reported.

Jun 18 2021 - 9:58am

S63845

Probe Availability

Probe Information

Target Details

BCL2 family apoptosis regulator, BCL2L3, EAT-ES, MCL1L, MCL1S, Mcl-1, TM, bcl2-L-3, mcl1/EAT, MCL1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

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S63845

Probe Availability

Probe Information

Target Details

BCL2 family apoptosis regulator, BCL2L3, EAT-ES, MCL1L, MCL1S, Mcl-1, TM, bcl2-L-3, mcl1/EAT, MCL1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?