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 drug discovery.<br/>Here we describe our efforts leading to the discovery of the first inhibitors. Hit to lead chemistry identified compound 4 showing potent inhibition of the ATPase activity of Tip48/Tip49 and potent growth inhibitory activity against Ramos cells (human Burkitt's lymphoma) (Figure 1). However, oral administration of compound 4 showed a poor PK profile as well as poor PD response in subcutaneous models of Burkitt’s lymphoma probably due to its poor aqueous solubility. As such, our approach is to introduce a basic group into the molecule so as to improve solubility while maintaining potency. After extensive medicinal chemistry efforts, we finally discovered potent Tip48/Tip49 inhibitors DS71290859 and DS31540255 bearing a solubilizing amino group. Oral dosing of these compounds resulted in a robust tumor growth inhibition associated with clear upregulation of p21 mRNA level in subcutaneous models of Burkitt’s lymphoma without any severe toxicity profile at tested dose levels. In addition, they demonstrated acceptable ADME profile and drug-like properties including metabolic stability and solubility.

Tip48/Tip49 inhibitors: Antipyrine derivatives with diamide linker as potential anticancer agents

2019 Spring National Meeting

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