S63845

Biological Activity

In vitro: The pro-survival protein myeloid cell leukemia 1 (MCL1) is over expressed in many cancers. S63845 is a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. The activity of S63845 is next evaluated in a panel of eight AML cell lines: all lines are sensitive to S63845 (IC50=4-233 nM). In vivo: S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Intravenously injected (i.v.) S63845 exerts dose-dependent anti-tumour activity in human multiple myeloma (H929 and AMO1) xenografts in immunocompromised mice, with maximal tumour growth inhibition of 114% in the AMO1 model and 103% in the H929 model. At 25 mg/kg, S63845 induces complete regression in 7 out of 8 of the mice at 100 days after treatment in the AMO1 model.

Product Citations

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  Cancers (Basel). 2021 May 12;13(10):2310.

  Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA
  S63845 purchased from AbMole

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  Mol Carcinog. 2020 Nov;59(11):1256-1268.

  Mcl-1 targeting strategies unlock the proapoptotic potential of TRAIL in melanoma cells
  S63845 purchased from AbMole

Customer Product Validations & Biological Datas

	Source	MOL CARCINOGEN 2020. Figure 5. S63845 (Abmole Bioscience, USA)
	Method	Cell culture
	Cell Lines	Origin of human melanoma cell lines
	Concentrations	5 µM
	Incubation Time	24 hours
	Results	When applied alone, S63845 resulted in 15% apoptosis induction and reduction of viable cells to 60%. The proapoptotic Bcl-2 proteins Bax and Bak were strongly activated by S63845 (44%).

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Letai A, et al. Cancer Cell. S63845, an MCL-1 Selective BH3 Mimetic: Another Arrow in Our Quiver.

[2] Kotschy A, et al. Nature. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.