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Thioridazine analogues for Myeloid lukemia treament

AMLcancerpediatric myeloid leukemiaTarget therapyThioridazine TDZ

Introduction

New thioridazine analogue compounds have been patented for the treatment of acute myeloid leukemia (AML) harboring the t(6; 11) (q27; q23) KMT2A/AFDN rearrangement, with the specific objective of reducing the side effects of the compound currently in use.

Technical features

Thioridazine (TDZ) is a novel targeted treatment for acute myeloid leukemia (AML) harboring the t(6;11)(q27;q23) rearrangement. Conventional chemotherapy for the treatment of this particular AML in the pediatric context does not yield a high survival rate.

TDZ provokes AML death through a cytoskeleton remodelling, aberrant Ca2+ influx, and mitochondrial apoptosis. The new thioridazine analogue compounds were tested to overcome the neuroleptic side effects of TDZ: they have reduced blood brain barrier crossing, while maintaining cytotoxicity over t(6;11) AML. These patented analogues have shown a selective cytotoxic activity towards this form of AML with virtually no damage to the central nervous system. The cytotoxicity is due to the increase of calcium influx, which leads to mitochondrial apoptosis cell death, a newly observed mechanism for this compound known mainly for its neuroleptic activity on the central nervous system.

The compounds have been tested in in vitro and in vivo settings. Experimentation will advance to pre-clinical data on acute myeloid leukemia patient-derived xenograft models that will be treated with the new compounds as single agents or in combination with chemotherapy. The compounds will be evaluated for cardiotoxicity, which has been described for the lead compound when used in human adults with acute myeloid leukemia.

Possible Applications

  • Treatment of acute myeloid leukemia (AML) with genetic lesion t(6;11)(q27;q23) KMT2A/AFDN.

Advantages

  • Highly cytotoxic towards AML with t(6;11)(q27;q23) KMT2A/AFDN;
  • Reduced central nervous system side effects;
  • Ideal for pediatric use.