Central nervous system lesions often cause permanent motility defects in mammals since the injured neurons cannot regenerate. In contrast, lower vertebrates like zebrafish can regenerate lost neurons and restore motor function. This study investigates the efficacy of SC79, a pan-Akt activator, and A674563, a selective Akt1 inhibitor, as potential therapeutic agents for promoting spinal cord recovery post-injury. Spinal cord injury was induced in zebrafish larvae, and the effects of SC79 and A674563 on neuronal and glial regeneration were examined. SC79 promoted neuronal regeneration without affecting glial bridging, while A674563 induced glial bridging but reduced neuronal regeneration. The combination of SC79 and A674563 induced both glial bridging and neuronal regeneration. Optomotor response tests revealed improved motor function recovery with the combined treatment compared to individual treatments. Additionally, these chemical treatments altered the expression of 12 Akt downstream transcriptional target genes, affirming that the combination treatment preferentially regulates spinal cord regeneration through its action on Akt signaling. These findings highlight the complex interplay of Akt signaling pathways in spinal cord regeneration and suggest potential therapeutic strategies for enhancing functional recovery in spinal cord injury patients.

2024-05-01·Clinical and Translational Medicine

DNA‐PKcs/AKT1 inhibits epithelial–mesenchymal transition during radiation‐induced pulmonary fibrosis by inducing ubiquitination and degradation of Twist1

Article

作者: Liu, Yuhao ; Zhou, Lin ; Gu, Yongqing ; Zhu, Jiaojiao ; Ao, Xingkun ; Chen, Huixi ; Zhou, Shenghui ; Wang, Ping ; Liang, Xinxin ; Li, Zhongqiu ; Zhou, Ping-Kun ; Hou, Yifan ; Yan, Ziyan ; Huang, Xin ; Gao, Shanshan

Abstract:

Introduction:

Radiation‐induced pulmonary fibrosis (RIPF) is a chronic, progressive, irreversible lung interstitial disease that develops after radiotherapy. Although several previous studies have focused on the mechanism of epithelial–mesenchymal transition (EMT) in lung epithelial cells, the essential factors involved in this process remain poorly understood. The DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs) exhibits strong repair capacity when cells undergo radiation‐induced damage; whether DNA‐PKcs regulates EMT during RIPF remains unclear.

Objectives:

To investigate the role and molecular mechanism of DNA‐PKcs in RIPF and provide an important theoretical basis for utilising DNA‐PKcs‐targeted drugs for preventing RIPF.

Methods:

DNA‐PKcs knockout (DPK−/−) mice were generated via the Cas9/sgRNA technique and subjected to whole chest ionizing radiation (IR) at a 20 Gy dose. Before whole chest IR, the mice were intragastrically administered the DNA‐PKcs‐targeted drug VND3207. Lung tissues were collected at 1 and 5 months after IR.

Results:

The expression of DNA‐PKcs is low in pulmonary fibrosis (PF) patients. DNA‐PKcs deficiency significantly exacerbated RIPF by promoting EMT in lung epithelial cells. Mechanistically, DNA‐PKcs deletion by shRNA or inhibitor NU7441 maintained the protein stability of Twist1. Furthermore, AKT1 mediated the interaction between DNA‐PKcs and Twist1. High Twist1 expression and EMT‐associated changes caused by DNA‐PKcs deletion were blocked by insulin‐like growth factor‐1 (IGF‐1), an AKT1 agonist. The radioprotective drug VND3207 prevented IR‐induced EMT and alleviated RIPF in mice by stimulating the kinase activity of DNA‐PKcs.

Conclusion:

Our study clarified the critical role and mechanism of DNA‐PKcs in RIPF and showed that it could be a potential target for preventing RIPF.

2024-03-03·Expert opinion on therapeutic patents

Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020–2023)

Review

作者: Hajjo, Rima ; Bardaweel, Sanaa K. ; Zhong, Haizhen A. ; Sabbah, Dima A.

INTRODUCTION:

Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed.

AREA COVERED:

This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023.

EXPERT OPINION:

To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.

项与 NISC-6 相关的新闻（医药）

2024-10-23

·PipelineReview

Atavistik Bio Presents Preclinical Data on Precision Oncology Development Candidate, ATV-1601, a Selective Allosteric AKT1 E17K Small Molecule Inhibitor, at EORTC-NCI-AACR Symposium

CAMBRIDGE, MA, USA I October 23, 2024 I Atavistik Bio, a biotechnology company discovering the next generation of precision allosteric therapeutics inspired by the body’s natural regulators, today presented preclinical data at the 36 th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Meeting 2024 in Barcelona for ATV-1601, the company’s orally bioavailable selective allosteric small molecule inhibitor for AKT1 E17K-driven cancers. The preclinical data demonstrated that as a selective allosteric AKT1 E17K inhibitor, ATV-1601 provides enhanced target inhibition, superior efficacy and improved tolerability compared to pan-AKT inhibitors in preclinical models. Atavistik Bio anticipates initiating a first-in-human study with ATV-1601 in patients with AKT1 E17K mutant tumors in early 2025. AKT1 E17K is a clinically validated oncogene that impacts greater than 40,000 cancer patients per year in the United States, with the highest prevalence in breast, endometrial, and prostate cancers. In addition, early evidence indicates that the AKT1 E17K mutation appears to be an emerging mechanism of resistance to PI3Kα-targeted cancer therapies. The only approved AKT-targeted therapy is a pan-AKT inhibitor that blocks all three isoforms of AKT (AKT1, AKT2, and AKT3). Pan-AKT inhibitors offer limited efficacy for patients with AKT1 E17K-driven mutant tumors due to insufficient inhibition of the AKT1 E17K mutation. Additionally, pan-AKT inhibitors can cause significant adverse events, such as AKT2-driven hyperglycemia, rash, and diarrhea, which lead to treatment discontinuation or dose reductions in a considerable subset of patients. Data presented in today’s poster entitled, “ATV-1601 is a Potent and Selective Allosteric Inhibitor of AKT1 E17K and Shows Profound and Durable Regressions in AKT1 E17K-Driven Patient-Derived Xenograft Models,” demonstrates that the selectivity profile of ATV-1601 enables greater than 90% target engagement without inducing hyperglycemia in preclinical models. As a result of this potent target engagement and selectivity, ATV-1601 demonstrated profound and durable tumor regression in multiple AKT1 E17K driven patient-derived breast and endometrial tumor models and was well tolerated. “We are pleased to share these exciting preclinical data for our ATV-1601 program with the oncology community,” said Marion Dorsch, Ph.D., President and Chief Scientific Officer, Atavistik Bio. “As a selective allosteric AKT1 E17K inhibitor, ATV-1601 has the potential to be a transformative precision therapy against the validated AKT1 E17K oncogenic driver. The patient populations impacted by the AKT1 E17K mutation have a significant unmet need, which we are working with urgency to address. We look forward to transitioning into the clinic in our planned first-in-human study.” About Atavistik Bio Atavistik Bio is a biotechnology company accelerating the discovery and development of transformative precision allosteric therapeutics to address serious unmet patient needs, with a focus on oncology. Atavistik Bio is led by an experienced team of drug hunters with a proven track record of developing marketed small molecule therapies and supported by top-tier investors, including The Column Group, Nextech Invest, and Lux Capital. To learn more, visit us at atavistikbio.com and follow us on LinkedIn . SOURCE: Atavistik Bio

AACR会议

2024-10-15

·GlobeNewswire-Health Care

Atavistik Bio Announces Nomination of Precision Oncology Development Candidate, ATV-1601, a Selective Allosteric AKT1 E17K Small Molecule Inhibitor

AKT1 E17K mutation is a clinically validated oncogene that impacts greater than 40,000 cancer patients per year in the United States, with the highest prevalence in breast, endometrial, and prostate cancersAs a selective allosteric AKT1 E17K inhibitor, ATV-1601 has the potential to provide enhanced target inhibition, superior efficacy and improved tolerability compared to pan-AKT inhibitorsAtavistik Bio anticipates initiating a first-in-human study with ATV-1601 in patients with AKT1 E17K mutant tumors in early 2025Preclinical data on ATV-1601 to be presented at the EORTC-NCI-AACR Symposium on October 23, 2024The company continues to leverage the AMPS™ platform to bring forward additional high-value precision oncology programs CAMBRIDGE, Mass., Oct. 15, 2024 (GLOBE NEWSWIRE) -- Atavistik Bio, a biotechnology company discovering the next generation of precision allosteric therapeutics inspired by the body’s natural regulators, today announced its precision oncology development candidate ATV-1601, an orally bioavailable selective allosteric small molecule inhibitor for AKT1 E17K-driven cancers. ATV-1601 was developed leveraging the company’s AMPS™ technology, which is seamlessly integrated with its AI-enabled drug discovery engine to rapidly advance programs from discovery into development. “ATV-1601’s nomination as our first oncology development candidate is a major milestone for the company, validating the capabilities of our proprietary platform to rapidly discover and advance novel precision allosteric therapeutics for targets that have historically been hard to drug. We anticipate significant progress in our portfolio in the upcoming year for high value oncology targets that address the unmet needs of large patient populations,” said Bryan Stuart, Chief Executive Officer, Atavistik Bio. “We are working to quickly advance ATV-1601 to the clinic and to achieve early clinical proof of concept for this program. We believe our precision allosteric small molecule offers several advantages to target the difficult-to-drug AKT1 E17K mutation, with the potential to improve the lives of many cancer patients.” AKT1 E17K mutation is a clinically validated oncogene that impacts greater than 40,000 cancer patients per year in the United States, with the highest prevalence in breast, endometrial, and prostate cancers. In addition, early evidence indicates that the AKT1 E17K mutation appears to be an emerging mechanism of resistance to PI3Kα-targeted cancer therapies. A selective allosteric AKT1 E17K inhibitor has the potential to be a transformative therapy against the validated AKT1 E17K oncogenic driver as well as resistance mutations emerging from PI3Kα-targeted therapies. The only approved AKT-targeted therapy is a pan-AKT inhibitor that blocks all three isoforms of AKT (AKT1, AKT2, and AKT3). Pan-AKT inhibitors offer limited efficacy for patients with AKT1 E17K-driven mutant tumors due to insufficient inhibition of the AKT1 E17K mutation. Additionally, pan-AKT inhibitors can cause significant adverse events, such as AKT2-driven hyperglycemia, rash, and diarrhea, which leads to treatment discontinuation or dose-reductions in a considerable subset of patients. ATV-1601, a selective allosteric AKT1 E17K inhibitor, has the potential to provide enhanced target inhibition, superior efficacy and improved tolerability compared to pan-AKT inhibitors for AKT1 E17K-driven cancers. Atavistik Bio anticipates initiating a first-in-human study with ATV-1601 in patients with AKT1 E17K-mutant tumors in early 2025. “Behind ATV-1601, we have a robust pipeline of precision oncology programs derived from our AMPS platform, said Marion Dorsch, Ph.D., President and Chief Scientific Officer, Atavistik Bio. “We look forward to advancing our internal pipeline with urgency while also broadening the reach of our platform through partnerships to discover important new allosteric therapeutics across other diseases.” Atavistik Bio EORTC-NCI-AACR Symposium Data Presentation Details Date:Wed., October 23, 2024Time:12.00 – 19.00 CETPoster Session:New DrugsPoster Title:ATV-1601 is a Potent and Selective Allosteric Inhibitor of AKT1 E17K and Shows Profound and Durable Regressions in AKT1 E17K-Driven Patient-Derived Xenograft ModelsPoster #:PB128 About Atavistik Bio Atavistik Bio is a biotechnology company accelerating the discovery and development of transformative precision allosteric therapeutics to address serious unmet patient needs, with a focus on oncology. Atavistik Bio is led by an experienced team of drug hunters with a proven track record of developing marketed small molecule therapies and supported by top-tier investors, including The Column Group, Nextech Invest, and Lux Capital. To learn more, visit us at atavistikbio.com and follow us on LinkedIn. Media Contact: Liz MeloneMelone Communications, LLCliz@melonecomm.com

临床研究AACR会议

2024-04-03

·BioSpace

Alterome Therapeutics Raises $132 Million in Series B Financing Led by Goldman Sachs Alternatives

Proceeds support advancement of two next-generation precision oncology programs into clinical development within 12 months Financing led by Goldman Sachs Alternatives with participation by Canaan Partners, Driehaus Capital Management, Invus, Digitalis Ventures, Blue Owl Capital, and existing investors SAN DIEGO--(BUSINESS WIRE)-- Alterome Therapeutics, Inc., a biopharmaceutical company pioneering the development of next generation, small molecule targeted therapies for the treatment of cancer, today announced the closing of a $132 million Series B financing. Proceeds from the fundraise will be used to support the advancement of multiple wholly-owned pipeline programs into the clinic, including a highly specific AKT1 E17K inhibitor and a KRAS selective inhibitor. The financing was led by Goldman Sachs Alternatives, with participation by Canaan Partners, Invus, Driehaus Capital Management, Digitalis Ventures, Blue Owl Capital, and existing investors Orbimed, Nextech Invest, Vida Ventures, Boxer Capital, and Colt Ventures. Concurrent with the financing, Josh Richardson, M.D., a Managing Director within Life Sciences Investing at Goldman Sachs Alternatives, and Uwe Schoenbeck, a Partner at Canaan Partners, were named to the Board of Directors. “We are pleased with a financing of this magnitude that enables Alterome to advance multiple programs into the clinic within the next 12 months,” said Eric Murphy, Ph.D., co-founder and CEO of Alterome Therapeutics. “The precision oncology field has arrived at a special moment with the exciting evolution of both drug discovery and precision medicine. A unique integration of structure-guided drug discovery with deep translational biology is facilitating the development of novel therapies that address previously inaccessible proteins. We are thrilled to have the support of this visionary group of new and existing investors, who share our enthusiasm to face the challenge of targeting well-known cancer-causing mutations deemed undruggable for the previous 20 years.” Leveraging its Kraken platform, a structure-guided machine learning approach to drug discovery, the company is advancing a pipeline of precision, small molecule therapies targeting a broad spectrum of validated oncogenic targets. Alterome’s founding mission focused on mutation-selective and isoform-selective approaches designed to specifically target cancer cells over normal cells, enabling greater inhibition of key cancer drivers while simultaneously enhancing the therapeutic safety profile. The preclinical pipeline features a covalent AKT1 E17K mutation-selective inhibitor and a KRAS isoform-selective inhibitor targeting 90% of KRAS mutations including the most common mutations G12V and G12D. These two lead programs are designed for patients with limited treatment options and are expected to begin clinical testing over the next year. “Alterome is advancing an exciting portfolio of therapies targeting validated oncogenic drivers, with clear paths to early clinical signals,” said Dr. Josh Richardson, Managing Director within Life Sciences Investing at Goldman Sachs Alternatives. “Goldman Sachs is excited to join this exceptional group of investors to support the company in delivering a new class of precision oncology drugs that enable cancer patients to live longer and better lives.” About Alterome Therapeutics, Inc. Alterome Therapeutics, Inc. is a precision oncology biotech developing alteration-specific therapeutics to address high-value and validated oncogenic drivers. The company is led by an expert team of precision oncology R&D leaders with a history of developing marketed oncology small molecule drugs. For more information, visit . Follow us on LinkedIn and Twitter. About Goldman Sachs Alternatives Goldman Sachs (NYSE: GS) is one of the leading investors in alternatives globally, with over $450 billion in assets and more than 30 years of experience. The business invests in the full spectrum of alternatives including private equity, growth equity, life sciences, private credit, real estate, infrastructure, hedge funds, and sustainability. Clients access these solutions through direct strategies, customized partnerships, and open-architecture programs. The business is driven by a focus on partnership and shared success with its clients, seeking to deliver long-term investment performance drawing on its global network and deep expertise across industries and markets. The alternative investments platform is part of Goldman Sachs Asset Management, which delivers investment and advisory services across public and private markets for the world’s leading institutions, financial advisors, and individuals. Goldman Sachs has over $2.8 trillion in assets under supervision globally as of December 31, 2023. Follow us on LinkedIn. View source version on businesswire.com: Contacts Investors: Scott Moorefield Alterome Therapeutics Scott@alterome.com Media: Sarah Sutton Argot Partners 212-600-1902 alterome@argotpartners.com Source: Alterome Therapeutics, Inc. View this news release online at:

100 项与 NISC-6 相关的药物交易

登录后查看更多信息