A Phthalimide Derivative That Inhibits Centrosomal Clustering Is Effective on Multiple Myeloma

Abstract

Despite the introduction of newly developed drugs such as lenalidomide and bortezomib, patients with multiple myeloma are still difficult to treat and have a poor prognosis. In order to find novel drugs that are effective for multiple myeloma, we tested the antitumor activity of 29 phthalimide derivatives against several multiple myeloma cell lines. Among these derivatives, 2-(2,6-diisopropylphenyl)-5-amino-1 H -isoindole-1,3- dione (TC11) was found to be a potent inhibitor of tumor cell proliferation and an inducer of apoptosis via activation of caspase-3, 8 and 9. This compound also showed in vivo activity against multiple myeloma cell line KMS34 tumor xenografts in ICR/SCID mice. By means of mRNA display selection on a microfluidic chip, the target protein of TC11 was identified as nucleophosmin 1 (NPM). Binding of TC11 and NPM monomer was confirmed by surface plasmon resonance. Immunofluorescence and NPM knockdown studies in HeLa cells suggested that TC11 inhibits centrosomal clustering by inhibiting the centrosomal-regulatory function of NPM, thereby inducing multipolar mitotic cells, which undergo apoptosis. NPM may become a novel target for development of antitumor drugs active against multiple myeloma.

Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients

“…Centrosome amplification is common in MM and is associated with poor prognosis 25,26 . Furthermore, inhibition of centrosomal clustering may be effective in treatment of MM 27,28 . We found that germline variation that affects a gene involved in centrosomal function may also contribute to disease progression.…”

Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

“…McPherson and co‐workers constructed a library of mRNA‐displayed proteins from human liver, kidney, and bone marrow transcripts, and selected against biotinylated FK506 178. Recently, the successful target identification by mRNA display selection on a microfluidic chip was reported 179. Nucleophosmin was identified as the target protein of the phthalimide derivative 2‐(2,6‐diisopropylphenyl)‐5‐amino‐1 H ‐isoindole‐1,3‐dione (TC11, Table 1, entry 58).…”

The impact of mitotic errors on cell proliferation and tumorigenesis

“…HSET is not required for the growth of cells with the normal number of centrosomes but is required for the viability of tumor cells with extra centrosomes. This knowledge has sparked the development of a suite of new drugs that aim to destroy tumor cells with extra centrosomes by suppressing centrosome clustering (Rebacz et al 2007;Castiel et al 2011;Raab et al 2012;Shiheido et al 2012;Kawamura et al 2013;Pannu et al 2014;Bhakta-Guha et al 2015;Johannes et al 2015;Li et al 2015;Tan et al 2015;Zhang et al 2016). While these compounds have been shown to decluster centrosomes and induce lethal multipolar divisions in cell culture, whether these tumor-specific drugs achieve an enhanced therapeutic index and improved clinical efficacy remains to be determined.…”