Presentation Title

Targeting Musashi (MSI) Family of RNA Binding Proteins in Myeloid Leukemia

Faculty Mentor

Gerard Minuesa, Michael Kharas

Start Date

18-11-2017 10:00 AM

End Date

18-11-2017 10:15 AM

Location

9-273

Session

Bio Sciences 3

Type of Presentation

Oral Talk

Subject Area

health_nutrition_clinical_science

Abstract

MUSASHI-2 (MSI2), one of the two members of the RNA-binding protein MUSASHI gene family, is highly expressed in hematopoietic stem cells, is required for their self-renewal program, and promotes a block in differentiation. Mechanistically, it is known as a translational regulator for several oncogenic and cell cycle related mRNAs including cMYC, HOXA9, IKZF2 or CDKN1. In accordance, MSI2 aberrant overexpression has been associated with Acute Myeloid Leukemia (AML) poor prognosis and lower survival rate. Here, we aimed to develop a small molecule inhibitor of MSI2 function as a novel therapeutic approach to tackle AML. Inhibiting MSI2 function results in reduced proliferation, differentiation and apoptosis of AML cells lines, which could result in improved survival or eradication of the leukemia. A 160K compound screen initially identified the parent compound NCI#12 as a selective and potent MSI inhibitor. In partnership with Tri-Institutional Drug Discovery Initiative, analogs of the compound were synthesized and tested for their affinity to MSI2/RNA complexes, their cytotoxic effects on human leukemic cells and their effect on MSI2 mRNA and protein targets. Among the TDI tested, TDI4882 was found to be the most selective and potent compound showing high affinity interaction and inhibition of MSI2/RNA complexes, EC50 below 10 μM and a significant inhibition effect on cMYC protein levels. Although the specific inhibition mechanism still needs to be elucidated, it is the most promising compound to be tested in vivo models of leukemia in the lab.

Summary of research results to be presented

Finding a small molecule with specificity for MSI2 RNA-binding protein could open new avenues in the therapeutic field of leukemia treatment. After running a large number of molecules in our FP-based screen, a chemical entity from NCI Chamical Library (NCI#12) with MSI2 selectivity and potency of RNA-binding activity inhibition was found. The results here presented show the analysis and validation of novel analogs synthesized from the parental NCI#12 compound. Among all the small molecules tested, TDI4882 showed the highest MSI2 inhibition potency: it abrogated the MSI2/RNA complex formation in EMSA, interacted with RRM1/RNA complexes, showed a cytotoxic effect and an effect on cMYC in MOLM13 leukemia cells. Further analysis of its effect on normal CD34+ stem cells derived from cord blood need to be done to assess its therapeutic window at the same effective doses. More TDI analogs are being synthesized and will be further tested with the same techniques here shown and will be compared to the current analysis. In addition, in collaboration with medicinal chemists and biocomputational labs from MSKCC, we are planning to obtain the docking model based on human MSI2 RRM1 crystal structure (previously solved in the lab) and attempt the crystal structure of RRM1 bound to RNA and the TDI compound. Moving forward, the most promising TDI compound will be tested in our established MLL-AF9 mouse model to understand the pharmacokinetics, toxicity, and effectiveness in vivo. This will help elucidate whether this compound can potentially be implemented in clincal trials with leukemia patients.

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Nov 18th, 10:00 AM Nov 18th, 10:15 AM

Targeting Musashi (MSI) Family of RNA Binding Proteins in Myeloid Leukemia

9-273

MUSASHI-2 (MSI2), one of the two members of the RNA-binding protein MUSASHI gene family, is highly expressed in hematopoietic stem cells, is required for their self-renewal program, and promotes a block in differentiation. Mechanistically, it is known as a translational regulator for several oncogenic and cell cycle related mRNAs including cMYC, HOXA9, IKZF2 or CDKN1. In accordance, MSI2 aberrant overexpression has been associated with Acute Myeloid Leukemia (AML) poor prognosis and lower survival rate. Here, we aimed to develop a small molecule inhibitor of MSI2 function as a novel therapeutic approach to tackle AML. Inhibiting MSI2 function results in reduced proliferation, differentiation and apoptosis of AML cells lines, which could result in improved survival or eradication of the leukemia. A 160K compound screen initially identified the parent compound NCI#12 as a selective and potent MSI inhibitor. In partnership with Tri-Institutional Drug Discovery Initiative, analogs of the compound were synthesized and tested for their affinity to MSI2/RNA complexes, their cytotoxic effects on human leukemic cells and their effect on MSI2 mRNA and protein targets. Among the TDI tested, TDI4882 was found to be the most selective and potent compound showing high affinity interaction and inhibition of MSI2/RNA complexes, EC50 below 10 μM and a significant inhibition effect on cMYC protein levels. Although the specific inhibition mechanism still needs to be elucidated, it is the most promising compound to be tested in vivo models of leukemia in the lab.