Ugi Reaction-Derived α‑Acyl Aminocarboxamides Bind to Phosphatidylinositol 3‑Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells

Heat
shock transcription factor 1 (HSF1) has been identified as
a therapeutic target for pharmacological treatment of multiple myeloma
(MM). However, direct therapeutic targeting of HSF1 function seems
to be difficult due to the shortage of clinically suitable pharmacological
inhibitors. We utilized the Ugi multicomponent reaction to create
a small but smart library of α-acyl aminocarboxamides and evaluated
their ability to suppress heat shock response (HSR) in MM cells. Using
the INA-6 cell line as the MM model and the strictly HSF1-dependent
HSP72 induction as a HSR model, we identified potential HSF1 inhibitors.
Mass spectrometry-based affinity capture experiments with biotin-linked
derivatives revealed a number of target proteins and complexes, which
exhibit an armadillo domain. Also, four members of the tumor-promoting
and HSF1-associated phosphatidylinositol 3-kinase-related kinase (PIKK)
family were identified. The antitumor activity was evaluated, showing
that treatment with the anti-HSF1 compounds strongly induced apoptotic
cell death in MM cells.