Tip48 and Tip49 are two related and highly conserved eukaryotic AAA+ proteins (ATPases associated with various cellular activities) with an essential biological function and a critical role in major pathways that are closely linked to cancer. Small molecule inhibitors of Tip48/Tip49 are therefore considered attractive for anticancer treatment. Here we describe our efforts to discover DS11280655 including research background, structure activity relationship (SAR) and in vivo evaluation of the compound. We had already obtained compound 3 through hit-to-lead optimization. Compound 3 showed potent inhibition of the ATPase activity of Tip48/Tip49 and potent growth inhibitory activity against Ramos cells (human Burkitt's lymphoma). However, compound 3 did not show in vivo pharmacological activity when dosed as a suspension in 0.5% methylcellulose solution (MC) because of its poor solubility. To obtain good PK profiles by improvement of solubility, we tried a scaffold hopping approach to convert an amide moiety of the linker part of compound 3 into an oxadiazole ring. This resulted in the discovery of DS11280655, which showed potent in vitro activity and a good PK profile when dosed as a suspension in MC. Furthermore, oral dosing of DS11280655 in the suspension exhibited a robust tumor growth inhibition in subcutaneous models of Burkitt’s lymphoma without significant body weight loss at tested dose levels.

Tip48/Tip49 inhibitors: Antipyrine derivatives with an oxadiazole ring as potential anticancer agents

2019 Spring National Meeting

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