A Master Protocol for the Multi-Cohort, Phase 1/2 Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies

This is a Phase 1/2, multicenter, open-label (unless otherwise specified in a combination-specific module) study of DCC-3116 in combination with anticancer therapies. Modules within the master protocol are defined according to different combinations of DCC-3116 with other anticancer agents.

开始日期2023-09-28

申办/合作机构

Deciphera Pharmaceuticals, Inc.

NCT04892017 / Recruiting临床1/2期

A Phase 1/2, First-in-Human Study of DCC-3116 as Monotherapy and in Combination With RAS/MAPK Pathway Inhibitors in Patients With Advanced or Metastatic Solid Tumors With RAS/MAPK Pathway Mutations

This is a Phase 1/2, multicenter, open label, first in human (FIH) study of DCC-3116 as monotherapy, and in combination with trametinib, binimetinib, or sotorasib in patients with advanced or metastatic solid tumors with RAS/MAPK pathway mutation. The study consists of 2 parts, a dose-escalation phase, and an expansion phase.

开始日期2021-06-15

申办/合作机构

Deciphera Pharmaceuticals, Inc.

100 项与 ULK2 x ULK1 相关的临床结果

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100 项与 ULK2 x ULK1 相关的转化医学

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0 项与 ULK2 x ULK1 相关的专利（医药）

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项与 ULK2 x ULK1 相关的文献（医药）

2024-11-01·Aquatic Toxicology

Nano-alumina induced developmental and neurobehavioral toxicity in the early life stage of zebrafish, associated with mTOR

Article

作者: He, Kaihong ; Wang, Yanhong ; Chen, Jianping ; Chen, Jin ; Zhang, Ping ; Zhang, Ling ; Guo, Xinyue ; Shang, Nan ; Niu, Qiao ; Zhang, Ying ; Zhang, Qinli

The study aims to investigate the effects of nano-alumina (AlNPs) on the early development and neurobehavior of zebrafish and the role of mTOR in this process. After embryos and grown-up larvae exposed to AlNPs from 0 to 200 μg/mL, we examined the development, neurobehavior, AlNPs content, and mTOR pathway genes. Moreover, embryos were randomly administered with control, negative control, mTOR knockdown, AlNPs, and mTOR knockdown + AlNPs, then examined for development, neurobehavior, oxidative stress, neurotransmitters, and development genes. As AlNPs increased, swimming speed and distance initially increased and then decreased; thigmotaxis and panic-avoidance reflex substantially decreased in the high-dose AlNPs group; aluminum and nanoparticles considerably accumulated in the 100 μg/mL AlNPs group; AlNPs at high dose decreased mTOR gene and protein levels, stimulating autophagy via increasing ULK1 and ULK2. mTOR knockdown exacerbated the harm to normal development rate, eye and body length, and neurobehavior induced by AlNPs through raising ROS, SOD, and ACH levels but decreasing AchE activity and development genes. Therefore, AlNPs suppress neurobehavior through downregulating mTOR, and mTOR knockdown further aggravates their early development and neurobehavior loss, suggesting mTOR could be a potential target for the toxicity of AlNPs.

2024-08-02·Future Medicinal Chemistry

A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer

Article

作者: Wai, Lam Kok ; Fasihi Mohd Aluwi, Mohd Fadhlizil ; Rungrotmongkol, Thanyada ; Ilowefah, Muna Abdulsalam ; Leong, Sze-Wei ; Mohd Faudzi, Siti Munirah ; Alshwyeh, Hussah Abdullah ; Islami, Deri ; Alosaimi, Areej A ; Mediani, Ahmed ; Haris, Muhammad Salahuddin ; Chia, Suet Lin ; Taher, Muhammad ; Koeberle, Andreas ; Shamsudin, Nur Farisya ; Rullah, Kamal ; Suriya, Utid

Aim: Chromones are promising for anticancer drug development.Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC₅₀ 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC₅₀ 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1.Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.

2024-08-01·Chinese Clinical Oncology

AB060. Autophagy-associated biomarkers ULK2, UVRAG, and miRNAs miR-21, miR-126, and miR-374: prognostic significance in glioma patients

Article

作者: Amin, Wajiha ; Sufiyan, Sufiyan ; Naeem, Sana ; Abidi, Syed Hani ; Ilyas, Sahar ; Enam, Syed Ather ; Uddin, Siraj ; Mughal, Nouman

BACKGROUNDAutophagy is a self-renewing process of the cell having a dual role in gliomagenesis depending on the tumor stage. Several microRNAs play a key role in the regulation of autophagy and the outcome of cancer. We investigated the potential relevance of autophagy in gliomagenesis and survival by exploring the association of the basal gene expression of autophagy-associated markers LC3, ULK1/2, UVRAG, Beclin1, mTOR, UVRAG, PI3K, AKT, PTEN and their target microRNAs miR-126, miR-374, miR-21, miR-7, miR-204 and miR-100 in low- and high-grades of gliomas.METHODSA total of 50 fresh glioma tissues were used for the extraction of RNA using TRIzol-Chloroform method and reverse transcribed cDNA. The cDNA was used to determine the expression of genes and microRNAs using quantitative real-time polymerase chain reaction (qPCR). Mann-Whitney U-test was used to determine the statistical significance.RESULTSIn high-grade glioma, increased expression of AKT and miR-21, coupled with reduced ULK2 and LC3 expression was distinctly observed. While correlation analysis identified a strong positive correlation between ULK2 and UVRAG, PTEN, miR-7, and miR-100 and a moderate positive correlation emerged between ULK2 and mTOR, miR-7, miR-30, miR-100, miR-204, and miR-374, also between miR-21 and miR-126 in low-grade glioma. Similarly, a positive correlation appeared between ULK2 and AKT, LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7 and miR-374. AKT positively correlated with LC3, PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, miR-7, miR-30, miR-204, miR-374, miR-126 and miR-21 weakly correlated with AKT and miR-30 in high-grade glioma. The low ULK2, UVRAG, and miR-374 expression group exhibited significantly poor overall survival in glioma, while miR-21 over-expression indicated a poor prognosis in glioma patients.CONCLUSIONSThis study provides comprehensive insights into the molecular landscape of gliomas, highlighting the dysregulation of autophagy genes ULK2, and UVRAG and the associated miR-21, miR-126 and miR-374 as potential prognostic biomarkers and emphasizing their unique significance in shaping survival outcomes in gliomas patients.

项与 ULK2 x ULK1 相关的新闻（医药）

2024-04-29

·Firstwordpharma

Ono to expand oncology pipeline with $2.4B Deciphera purchase

Ono Pharmaceutical agreed to acquire Deciphera Pharmaceuticals for $25.60 per share in cash, representing a total equity value of $2.4 billion, bolstering the Japanese firm’s oncology portfolio. Deciphera’s sole marketed product is the KIT inhibitor Qinlock (ripretinib), whilst its pipeline includes the CSF1R inhibitor vimseltinib and the ULK inhibitor DCC-3116.Gyo Sagara, chief executive of Ono, said “we expect that this acquisition…will not only expand Ono's target oncology portfolio, but also accelerate Ono's business development in the [US] and Europe, and strengthen kinase drug discovery research.”Qinlock is approved in the US, EU and more than 40 markets as a fourth-line treatment for gastrointestinal stromal tumours (GIST). However, efforts to expand its use in earlier settings fell flat in 2021 when the drug failed to significantly prolong progression-free survival (PFS) in the Phase III INTRIGUE study against Pfizer's Sutent (sunitinib) in patients with second-line GIST.Deciphera is currently investigating Qinlock in the late-stage INSIGHT trial for second-line GIST patients with mutations in KIT exon 11 and 17 and/or 18 and the absence of mutations in KIT exon 9, 13, and/or 14. Meanwhile, vimseltinib is expected to be filed with regulators later this year after meeting the primary endpoint of the Phase III MOTION study in patients with tenosynovial giant cell tumours not amenable to surgery.The boards of both companies have unanimously approved the transaction, which is expected to close in the third quarter. The price of the deal represents a premium of 74.7% over Deciphera’s closing share price on April 26.

临床3期并购上市批准