Bcr-TMP, a Novel Nanomolar-Active Compound That Exhibits Both MYB- and Microtubule-Inhibitory Activity.

Maria V. Yusenko,Leonhard H. F. Köhler,Karl-Heinz Klempnauer,Cyrus Khandanpour,Bernhard Biersack,Rainer Schobert,Göran Stenman,Abhiruchi Biyanee,Daria Frank,Mattias K. Andersson

doi:10.3390/cancers14010043

Abstract

Simple SummaryRecent work has identified the transcription regulator MYB as an interesting therapeutic target for the treatment of certain leukemias and other cancers that are dependent on deregulated MYB activity, such as acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Here we report the identification and characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (Bcr-TMP), a novel highly active MYB inhibitory compound. We show that nanomolar concentrations of Bcr-TMP are sufficient to down-regulate the expression of MYB target genes and induce both cell-death and differentiation in AML cell lines. Importantly, Bcr-TMP also and exerts stronger anti-proliferative effects on MYB-addicted primary AML cells and patient-derived ACC cells than on their non-oncogenic counterparts. Preliminary work shows that Bcr-TMP acts through p300, a protein interacting with MYB and stimulating its activity. Interestingly, Bcr-TMP has an additional activity as an anti-microtubule agent. Overall, Bcr-TMP is an interesting compound that warrants further research to understand its mechanism of action and its therapeutic potential for MYB-dependent malignancies.Studies of the role of MYB in human malignancies have highlighted MYB as a potential drug target for acute myeloid leukemia (AML) and adenoid cystic carcinoma (ACC). Here, we present the initial characterization of 2-amino-4-(3,4,5-trimethoxyphenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (Bcr-TMP), a nanomolar-active MYB-inhibitory compound identified in a screen for novel MYB inhibitors. Bcr-TMP affects MYB function in a dual manner by inducing its degradation and suppressing its transactivation potential by disrupting its cooperation with co-activator p300. Bcr-TMP also interferes with the p300-dependent stimulation of C/EBPβ, a transcription factor co-operating with MYB in myeloid cells, indicating that Bcr-TMP is a p300-inhibitor. Bcr-TMP reduces the viability of AML cell lines at nanomolar concentrations and induces cell-death and expression of myeloid differentiation markers. It also down-regulates the expression of MYB target genes and exerts stronger anti-proliferative effects on MYB-addicted primary murine AML cells and patient-derived ACC cells than on their non-oncogenic counterparts. Surprisingly, we observed that Bcr-TMP also has microtubule-disrupting activity, pointing to a possible link between MYB-activity and microtubule stability. Overall, Bcr-TMP is a highly potent multifunctional MYB-inhibitory agent that warrants further investigation of its therapeutic potential and mechanism(s) of action.

Highlights

MYB is the founding member of the MYB family of oncogenic transcription factors, which consists of MYB, MYBL1, and MYBL2 in vertebrate species [1,2,3]
We considered acetylation of MYB unlikely to play a major role in the inhibitory mechanism because the C-terminally truncated MYB-CT3 is clearly inhibited lacks these acetylation sites
As a first step to address this question we examined its effect on the activity of C/EBPβ, a transcription factor known to bind to the Taz2 domain of p300 [52]

Summary

Introduction

MYB is the founding member of the MYB family of oncogenic transcription factors, which consists of MYB, MYBL1, and MYBL2 in vertebrate species [1,2,3]. MYB is most highly expressed in hematopoietic progenitor cells where it acts as a master regulator of gene expression programs to control the development and homeostasis of the hematopoietic system. The MYB protein features an N-terminal DNA-binding domain recognizing a short nucleotide binding motif [6], a centrally-located transactivation domain that stimulates the transcription of target genes [7,8], and C-terminal regulatory sequences that are post-translationally modified by phosphorylation, acetylation, and sumo-conjugation [9,10,11,12]. MYB is highly dependent on cooperation with the co-activator p300/CBP, which binds via its KIX-domain to a conserved. LXXLL-motif located in the MYB transactivation domain [13,14,15]. Mutations causing to amino acid replacements within or immediately adjacent to the LXXLL-motif, such as

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