3α-Aminocholestane

3α-Aminocholestane is an inhibitor of SH2 domain-containing inositol-5’-phosphatase 1 (SHP-1; IC₅₀ = ~2.5 µM).¹ It is selective for SHP-1 over SHP-2 and phosphatase and tensin homolog (PTEN; IC₅₀s = >20 µM). 3α-Aminocholestane induces hyperactivation of the tyrosine kinase SYK in patient-derived Ph⁺ acute lymphoblastic leukemia (ALL) cells and selectively induces cytotoxicity in these cells over mature B cell lymphoma cells. It reduces leukemia burden and increases survival in a tyrosine kinase inhibitor-resistant patient-derived Ph⁺ ALL mouse xenograft model when administered at a dose of 50 mg/kg. 3α-Aminocholestane reduces cell viability of OPM2 multiple myeloma (MM) cells in a concentration-dependent manner and of RPMI8226 MM cells when used at concentrations greater than or equal to 12.5 µM.² It halts the cell cycle at the G₀/G₁ or G₂/M stages in the highly proliferative OPM2 or less proliferative RPMI8226 cell lines, respectively. It induces apoptosis via activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) in OPM2 cells but not in RPMI8226 cells. 3α-Aminocholestane reduces tumor burden and increases survival in an OPM2 mouse xenograft model.

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1. Chen, Z., Shojaee, S., Buchner, M., et al. Signaling threscholds and negative B cell selection in acute lymphoblastic leukemia. Nature 521(7552), 357-361 (2015).

2. Fuhler, G.M., Brooks, R., Toms, B., et al. Therapeutic potential of SH2 domain-containing inositol-5'-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. Mol. Med. 18, 65-75 (2012).