1236199-60-2

EDO-S101 is a fusion molecule composed of the DNA alkylating agent bendamustine and the histone deacetylase (HDAC) inhibitor SAHA that inhibits class I and II HDACs (IC₅₀s = 9-107 nM for HDAC1-3, 6, 8, and 10). It inhibits HDAC activity in rat peripheral blood mononuclear cells (PBMCs) ex vivo by 90% following a single dose of 10 mg/kg. EDO-S101 also induces formation of DNA crosslinks and double-strand breaks in HL-60 cells. It reduces growth of multiple myeloma (MM) cell lines irrespective of p53 mutational status or established resistance to DNA alkylating agents (IC₅₀s = 1.6-4.8 μM). EDO-S101 also induces MM cell death ex vivo in bone marrow samples isolated from patients with early- and late-stage MM. In vivo, EDO-S101 (60 mg/kg per week) reduces tumor growth and prolongs survival in an MM1S end-stage mouse xenograft model. It also prolongs survival in a multidrug resistant Vk12653 mouse transplant model of refractory MM.

Tinostamustine (EDO-S101) is a pan HDAC inhibitor; inhibits HDAC6, HDAC1, HDAC2 and HDAC3 with IC50 values of 6 nM, 9 nM, 9 nM and 25 nM, respectively[1].

HDAC6: 6 nM (IC₅₀); HDAC1: 9 nM (IC₅₀); HDAC2: 9 nM (IC₅₀); HDAC3: 25 nM (IC₅₀); HDAC10: 72 nM (IC₅₀); HDAC8: 107 nM (IC₅₀)

[1] Mehrling T, et al. The Alkylating-HDAC Inhibition Fusion Principle: Taking Chemotherapy to the Next Level with the First in Class Molecule EDO-S101. Anticancer Agents Med Chem. 2016;16(1):20-8. DOI:10.2174/1871520615666150518092027