Delving into the Latest Updates on OTS-167 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

hMELK

Mechanism

MELK inhibitors(Maternal embryonic leucine zipper kinase inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal Diseases

Active Indication

Advanced breast cancerMetastatic breast cancerTriple Negative Breast Cancer

Inactive Indication

Acute Lymphoblastic LeukemiaAcute Myeloid LeukemiaKidney Neoplasms+ [5]

Originator Organization

OncoTherapy Science, Inc.

Active Organization

OncoTherapy Science, Inc.

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.

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.

15 Dec 2023·Cancer Research

Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase

Article

Author: Stauffer, Shaun R. ; Cortes Gomez, Eduardo ; Kumari, Sangeeta ; Ben-Salem, Salma ; Vaghela, Vishwa ; Zhang, Dingxiao ; Lee, Sanghee ; Muldong, Michelle ; Chauhan, Gaurav ; McKenney, Jesse ; Rawat, Chitra ; Macdonald, Jonathan D. ; Dehm, Scott M. ; Rabljenovic, Anja ; Su, Yixue ; Liu, Song ; Venkadakrishnan, Varadha Balaji ; Heemers, Hannelore V. ; Singh, Nidhi ; Jamieson, Christina A.M. ; Dahiya, Ujjwal R. ; Magi-Galluzzi, Cristina ; Zoubeidi, Amina ; Hu, Qiang ; Ghanem, Yara ; Nicolas, Marlo ; Bachour, Salam ; Valenzuela, Malyn May ; Willard, Belinda ; DePriest, Adam D. ; Kim, Hyun-Tae ; Klein, Eric A.

AbstractProstate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2–Skp2–p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression.Significance:The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression.See related commentary by Mishra et al., p. 4008

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	US	OncoTherapy Science, Inc.	29 May 2017
Metastatic breast cancer	Phase 1	US	OncoTherapy Science, Inc.	29 May 2017
Triple Negative Breast Cancer	Phase 1	US	OncoTherapy Science, Inc.	29 May 2017
Multiple Myeloma	Preclinical	JP	OncoTherapy Science, Inc.	26 Nov 2016
Acute Lymphoblastic Leukemia	Preclinical	US	OncoTherapy Science, Inc.	01 Apr 2016
Acute Myeloid Leukemia	Preclinical	US	OncoTherapy Science, Inc.	01 Apr 2016
Myelodysplastic Syndromes	Preclinical	US	OncoTherapy Science, Inc.	01 Apr 2016
Philadelphia chromosome positive chronic myelogenous leukemia	Preclinical	US	OncoTherapy Science, Inc.	01 Apr 2016
Kidney Neoplasms	Preclinical	JP	OncoTherapy Science, Inc.	-
Small Cell Lung Cancer	Preclinical	JP	OncoTherapy Science, Inc.	-