Delving into the Latest Updates on OTS-167 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

NLK x hMELK

Action

inhibitors

Mechanism

MELK inhibitors(Maternal embryonic leucine zipper kinase inhibitors), NLK inhibitors(nemo like kinase inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesCongenital Disorders+ [2]

Active Indication

Advanced breast cancerMetastatic breast cancerTriple Negative Breast Cancer+ [1]

Inactive Indication

Acute Lymphoblastic LeukemiaAcute Myeloid LeukemiaKidney Neoplasms+ [5]

Originator Organization

OncoTherapy Science, Inc.

Active Organization

OncoTherapy Science, Inc.

Stanford University School of Medicine

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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PURPOSEIn our previous study, Developmental endothelial locus-1 (Del-1) was a promising predictive marker for breast cancer. However, the downstream targets of Del-1 remain unknown. Here, we sought to discover a druggable target downstream of Del-1 and investigate the mechanism by which it regulates the course of breast cancer.METHODSTo investigate Del-1 downregulation effect on breast cancer, we performed transcriptome analysis using RNA sequencing of Del-1 knockdowned MDA-MB-231 cell line Plus, to investigate the expression of Del-1 and Maternal embryonic leucine zipper kinase (MELK), mRNA levels in eight different triple-Negative Breast Cancer (TNBC) cell lines were analyzed. High-throughput sequencing was performed on total RNA isolated. OTS167 was used for MELK inhibition. The effects of MELK on cell proliferation and invasion were determined using the MTT and Matrigel transwell assays. Furthermore, we examined MELK expression in breast cancer tissue.RESULTSDel-1 and MELK mRNA expression levels were significantly higher in the TNBC cell lines, MDA-MB-468, HCC-1806, and MBA-MB-231. Knocking down Del-1 with siRNA in HCC-1806 and MBA-MB-231 cells significantly decreased MELK expression and thus suggested a possible relationship between Del-1 and MELK. In MDA-MB-468 cells, a basal-like 1 TNBC cell line, OTS167 significantly inhibited breast cancer cell proliferation and promoted cell apoptosis. To further investigate the relationship between Del-1 and MELK, dual inhibition of both Del-1 and MELK was performed, which significantly reduced the viability of MDA-MB-468 and MBA-MB-231 cells.CONCLUSIONWe found that MELK acts downstream of Del-1 and is a promising druggable target, especially in basal-like and mesenchymal stem-like subtype.

27 Mar 2024·Briefings in Bioinformatics

AI identifies potent inducers of breast cancer stem cell differentiation based on adversarial learning from gene expression data

Article

Author: Li, Zhongxiao ; Napolitano, Antonella ; Fedele, Monica ; Napolitano, Francesco ; Gao, Xin

AbstractCancer stem cells (CSCs) are a subpopulation of cancer cells within tumors that exhibit stem-like properties and represent a potentially effective therapeutic target toward long-term remission by means of differentiation induction. By leveraging an artificial intelligence approach solely based on transcriptomics data, this study scored a large library of small molecules based on their predicted ability to induce differentiation in stem-like cells. In particular, a deep neural network model was trained using publicly available single-cell RNA-Seq data obtained from untreated human-induced pluripotent stem cells at various differentiation stages and subsequently utilized to screen drug-induced gene expression profiles from the Library of Integrated Network-based Cellular Signatures (LINCS) database. The challenge of adapting such different data domains was tackled by devising an adversarial learning approach that was able to effectively identify and remove domain-specific bias during the training phase. Experimental validation in MDA-MB-231 and MCF7 cells demonstrated the efficacy of five out of six tested molecules among those scored highest by the model. In particular, the efficacy of triptolide, OTS-167, quinacrine, granisetron and A-443654 offer a potential avenue for targeted therapies against breast CSCs.

01 Mar 2024·Molecular Therapy: Oncology

Targeting MELK improves PD-1 blockade efficiency in cervical cancer via enhancing antitumor immunity

Article

Author: Hu, Jinqiu ; Li, Yu ; Gao, Ling ; Wang, Dongjiao ; Zou, Fei

The balance between T helper 1 (Th1) and T helper 2 (Th2) has a critical function in determining intratumoral immune response and anti-PD-1 immunotherapy. The level of maternal embryonic leucine zipper kinase (MELK) is reported to correlate with infiltration of immune cells in cancers, but the underlying molecular mechanism is not clarified. In the present study, we aimed to elucidate the potential function of MELK in cervical cancer. We found that MELK was upregulated and played an oncogenic role in cervical cancer. MELK overexpression shifted Th1/Th2 balance toward Th2 predisposition in mouse cervical tumors in vivo and naive T cells from human PBMCs in vitro, whereas MELK knockdown exhibited opposite effects. MELK overexpression activated NF-κB signaling and promoted IL-6 secretion by cervical cancer cells. Depletion of IL-6 by neutralization antibodies abrogated the influence of MELK on Th1/Th2 balance. In addition, MELK modulated the antitumor activity of cytotoxic CD8⁺ T cells in cervical tumors, but depletion of Th2 cells by IL-4 neutralization abrogated this effect. Finally, MELK overexpression conferred tolerance to PD-1 blockade in cervical tumors, whereas targeting MELK by OTSSP167 significantly enhanced PD-1 blockade efficiency. Our data elucidated a novel role of MELK in regulating Th1/Th2 balance and anti-PD-1 immunotherapy in cervical cancer.

100 Deals associated with OTS-167

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced breast cancer	Phase 1	United States	OncoTherapy Science, Inc.	29 May 2017
Metastatic breast cancer	Phase 1	United States	OncoTherapy Science, Inc.	29 May 2017
Triple Negative Breast Cancer	Phase 1	United States	OncoTherapy Science, Inc.	29 May 2017
Multiple Myeloma	Preclinical	Japan	OncoTherapy Science, Inc.	26 Nov 2016
Acute Lymphoblastic Leukemia	Preclinical	United States	OncoTherapy Science, Inc.	01 Apr 2016
Acute Myeloid Leukemia	Preclinical	United States	OncoTherapy Science, Inc.	01 Apr 2016
Myelodysplastic Syndromes	Preclinical	United States	OncoTherapy Science, Inc.	01 Apr 2016
Philadelphia chromosome positive chronic myelogenous leukemia	Preclinical	United States	OncoTherapy Science, Inc.	01 Apr 2016
Kidney Neoplasms	Preclinical	Japan	OncoTherapy Science, Inc.	-
Small Cell Lung Cancer	Preclinical	Japan	OncoTherapy Science, Inc.	-