MAX modulators(Max protein modulators), MYC modulators(Myc proto-oncogene protein modulators), RUNX1 antagonists(RUNX family transcription factor 1 antagonists)

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Myeloid Leukemia

Inactive Indication-

Originator Organization

Hannover Medical School

Active Organization

Hannover Medical School

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with MYCi361

100 Translational Medicine associated with MYCi361

100 Patents (Medical) associated with MYCi361

Literatures (Medical) associated with MYCi361

09 Mar 2023·Blood

RUNX1 isoform disequilibrium promotes the development of trisomy 21–associated myeloid leukemia

Article

Author: Ihling, Christian ; Yaspo, Marie-Laure ; Schuschel, Konstantin ; Kadel, Sofie-Katrin ; Ng, Michelle ; Labuhn, Maurice ; Verboon, Lonneke ; Heckl, Dirk ; Laszig, Stephanie ; Glaß, Markus ; Alejo-Valle, Oriol ; Gialesaki, Sofia ; Reinhardt, Dirk ; Hüttelmaier, Stefan ; Klusmann, Jan-Henning ; Regényi, Enikő ; Winkler, Robert ; Bräuer-Hartmann, Daniela ; Sinz, Andrea ; Matzk, Sören ; Strüwe, Farina Josepha ; Bhayadia, Raj ; Schmid, Lena ; Issa, Hasan ; Schmell, Anna-Lena

AbstractGain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR–CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

01 Nov 2019·Cancer Cell

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Article

Author: Vatapalli, Rajita ; Anker, Jonathan F ; Luan, Yi ; Lysy, Barbara ; Abdulkadir, Sarki A ; Schiltz, Gary E ; Mok, Hanlin ; Unno, Kenji ; Yoo, Young A ; Jain, Atul D ; Truica, Mihai I ; Chalmers, Zachary R ; Sagar, Vinay ; Rodriguez, Yara ; Han, Huiying ; Mishra, Rama K ; Izquierdo-Ferrer, Javier ; Kandela, Irawati ; Chakravarti, Debabrata ; Parker, J Brandon

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.

Frontiers in Cell and Developmental BiologyQ3 · BIOLOGY

Circular RNA circ_0057558 Controls Prostate Cancer Cell Proliferation Through Regulating miR-206/USP33/c-Myc Axis

Q3 · BIOLOGY

ArticleOA

Author: Zhang, Ping ; Ding, Tao ; Jin, Huimin ; Zheng, Jianghua ; Zhu, Yanjun ; Guo, Jianming

We previously reported the elevated expression of circ_0057558 in prostate cancer tissues and cell lines. Here, we aimed to determine the biological function of circ_0057558 in prostate cancer. In the current study, circ_0057558 knockdown in prostate cancer cells significantly repressed cell proliferation and colony formation, but promoted cell arrest and enhanced the sensitivity to docetaxel. Bioinformatics analysis prediction and RNA-pull down assay identified miR-206 as the potential binding miRNA of circ_0057558. A negative correlation was observed between the expression of miR-206 and circ_0057558 in prostate cancer tissues. miR-206 mimics rescued the function of circ_0057558 overexpression on prostate cancer cells. Further, the bioinformatics analysis and luciferase assay suggested that miR-206 may target ubiquitin-specific peptidase 33 (USP33). USP33 mRNA expression has negative correlation with miR-206 expression and positive correlation with circ_0057558 expression in prostate cancer tissues. USP33 overexpression partially blocked the effects of miR-206 mimics on prostate cell proliferation. USP33 could bind and deubiquitinate c-Myc. Increased c-Myc protein by circ_0057558 overexpression was partially reversed by miR-206 mimics. The proliferation inhibition activity of MYC inhibitor 361 (MYCi361) was more prominent in primary prostate cancer cells and patient-derived xenograft (PDX) model with higher level of circ_0057558. Collectively, circ_0057558 gives an impetus to cell proliferation and cell cycle control in prostate cancer cell lines by sponging miR-206 and positively regulating the transcription of the miR-206 target gene USP33.

100 Deals associated with MYCi361

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Indication	Highest Phase	Country/Location	Organization	Date
Myeloid Leukemia	Preclinical	DE	Hannover Medical School	08 Dec 2022

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