Matrix‐assisted laser desorption/ionization–imaging mass spectrometry (MALDI–IMS) is applied in drug discovery and development. A high‐throughput quantitative MALDI–IMS methodology was developed to confirm whether epertinib is superior to lapatinib in penetrating brain metastases using intraventricular injection mouse models (IVMs) of human EGFR2 (HER2)‐positive breast or T790M–EGFR‐positive lung cancer cells. A simple calibration curve was prepared for each compound via spotting standard solutions without using blank tissue sections or blank tissues onto the same glass slide as the epertinib or lapatinib brain section samples. Quantitative MALDI–IMS was performed via coating a glass slide with a MALDI matrix solution containing each internal standard solution. The samples of calibration curve and brain section were analyzed using a linear ion trap mass spectrometer with a MALDI ion source. Epertinib and lapatinib responses were strongly linear, with a wide dynamic range and low variation (relative standard deviation [RSD] < 20%) among the individual concentrations. Epertinib and lapatinib were sufficiently extracted from brain sections after oral administration in a breast cancer IVM. The quantitative MALDI–IMS results revealed that the epertinib concentrations administered to the brain sections in the lung cancer IVM were similar to those measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS). Quantitative MALDI–IMS, owing to its high reproducibility and throughput, is useful for selecting drug candidates in the early stages of discovery and development, enabling efficient and rapid screening of candidate compounds as well as an understanding of the mechanisms of drug efficacy, toxicity, and pharmacokinetics/pharmacodynamics.

2024-11-01·BIOMEDICINE & PHARMACOTHERAPY

Epertinib counteracts multidrug resistance in cancer cells by antagonizing the drug efflux function of ABCB1 and ABCG2

Article

作者: Huang, Yang-Hui ; Wu, Yu-Shan ; Li, Yen-Ching ; Hung, Tai-Ho ; Ambudkar, Suresh V ; Wu, Chung-Pu ; Murakami, Megumi ; Lin, Bing-Huan

A significant hurdle in cancer treatment arises from multidrug resistance (MDR), often due to overexpression of ATP-binding cassette (ABC) transporters like ABCB1 and/or ABCG2 in cancer cells. These transporters actively diminish the efficacy of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux and reducing intracellular drug accumulation in cancer cells. Addressing multidrug-resistant cancers poses a significant challenge due to the lack of approved treatments, prompting the exploration of alternative avenues like drug repurposing (also referred to as drug repositioning) of molecularly targeted agents to reverse MDR-mediated by ABCB1 and/or ABCG2 in multidrug-resistant cancer cells. Epertinib, a potent inhibitor of EGFR and HER2 currently in clinical trials for solid tumors, was investigated for its potential to resensitize ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our findings reveal that at sub-toxic, submicromolar concentrations, epertinib restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. The results demonstrate that epertinib enhances drug-induced apoptosis in these cancer cells by impeding the drug-efflux function of ABCB1 and ABCG2 without altering their expression. ATPase activity and molecular docking were employed to reveal potential interaction sites between epertinib and the drug-binding pockets of ABCB1 and ABCG2. In summary, our study demonstrates an additional pharmacological capability of epertinib against the activity of ABCB1 and ABCG2. These findings suggest that incorporating epertinib into combination therapy could be advantageous for a specific patient subset with tumors exhibiting high levels of ABCB1 or ABCG2, warranting further exploration.

2023-08-01·Journal of molecular modeling

Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies

Article

作者: Irajie, Cambyz ; Nezafat, Navid ; Mirmajidi, Seyedeh Habibeh ; Ghasemi, Younes ; Savardashtaki, Amir ; Negahdaripour, Manica

BACKGROUND:

The bacterium Bacillus coagulans has attracted interest because of its ability to produce spores and advantageous probiotic traits, such as facilitating food digestion in the intestine, managing some disorders, and controlling the symbiotic microbiota. Spore-forming probiotic bacteria are especially important in the probiotic industry compared to non-spore-forming bacteria due to their stability during production and high resistance to adverse factors such as stomach acid. When spore-forming bacteria are exposed to environmental stresses, they enter the sporulation pathway to survive. This pathway is activated by the final phosphorylation of the master regulator of spore response, Spo0A, and upon achieving the phosphorylation threshold. Spo0A is indirectly inhibited by some enzymes of the aspartate response regulator phosphatase (Rap) family, such as RapJ. RapJ is one of the most important Rap enzymes in the sporogenesis pathway, which is naturally inhibited by the pentapeptides.

METHODS:

This study used structure-based virtual screening and molecular dynamics (MD) simulation studies to find potential RapJ hits that could induce the sporulation pathway. The crystal structures of RapJ complexed with pentapeptide clearly elucidated their interactions with the enzyme active site.

RESULTS:

Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Among these compounds, acarbose obtained the highest score, especially in terms of the number of hydrogen bonds, which plays a major role in stabilizing RapJ-ligand complexes, and also according to the occupancy percentages of hydrogen bonds, its hydrogen bonds were more stable during the simulation time. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands.

项与艾培替尼相关的新闻（医药）

2025-12-04

·EINPresswire

Raya Therapeutic unveils its Raya CARES pipeline of five clinical-stage compounds

Each new chemical entity (NCE) has substantial clinical safety data and a unique mechanism of action to treat ALS, PD, and other neurodegenerative diseases. MONTREAL, QUEBEC, CANADA, December 4, 2025 / EINPresswire.com / -- Raya Therapeutic Inc., (“Raya”) a mission-driven company focused on the treatment of amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD) and other neurodegenerative diseases, announces the unveiling of its "Raya CARES" pipeline—a portfolio of five advanced clinical-stage compounds designed with differentiated mechanisms of action to address the multifactorial biology of neurodegenerative diseases. The Raya CARES pipeline includes Cutamesine, fAsudil, Rovatirelin, Epertinib and Smilagenin. It reflects Raya’s bold commitment to advancing therapies that protect neuronal health and survival. Each compound has a distinct mechanism of action, offering complementary approaches to slowing or halting disease progression. By leveraging compounds with established human safety data (each compound has completed at least Phase 2 development involving other CNS-related indications), Raya will accelerate their development. With financing, Raya expects to advance all five compounds into large Phase 2 or Phase 3 clinical trials within 12-18 months. Pipeline Overview RT1972 (Cutamesine) – Sigma-1 receptor agonist (S1RA) • RT1972 is neuroprotective by activating the sigma-1 receptor, a key regulator of endoplasmic reticulum–mitochondrial signaling. • This drug has already completed two Phase 2 trials in other CNS indications demonstrating blood-brain barrier (BBB) penetration and safety. • Raya believes that RT1972 is the most selective and potent S1RA in development and has potential in multiple indications including Parkinson’s, Alzheimer’s, Huntington’s and in other neurodegenerative and rare diseases. RT1968 (fAsudil) – ROCK (Rho-associated kinase) inhibitor • Fasudil modulates cytoskeletal dynamics, reduces neuroinflammation, and promotes axonal regeneration, targeting both neurons and glia in ALS. • By inhibiting ROCK, fasudil decreases microgliosis, enhances oligodendrocyte survival and remyelination. • Approved in Asia for cerebral vasospasm; extensive human safety record. • Demonstrated clinical proof of concept in a large Phase 2 study in people with ALS; the study results were published in The Lancet Neurology ( LINK ) in November 2024. RT2010 (Rovatirelin) – TRH (thyrotropin-releasing hormone) analog • Rovatirelin stimulates central nervous system pathways that enhance motor neuron outgrowth and provide protection. • Raya is collaborating with Shionogi & Co., Ltd. which discovered the drug and Kissei Pharmaceutical Co., Ltd. which is developing it in a Phase 3 confirmatory study in patients with spinocerebellar ataxia (SCA) that is expected to complete enrolling in March 2027. ( NCT07040137 ). RT1978 (Epertinib) – HER2/EGFR Tyrosine Kinase Inhibitor (TKI) • Originally developed as an oncology agent that completed Phase 1/2 clinical trial development, epertinib crosses the blood–brain barrier and modulates receptor tyrosine kinase signaling. • In neurodegeneration, this mechanism may promote neuronal survival through trophic signaling and stimulating autophagy as well as reducing abnormal glial activation. • Raya is collaborating with Shionogi & Co., Ltd., which discovered and initially developed the drug. RT1999 (Smilagenin) – Neurotrophic factor modulator • Orally active, non‑peptide inducer of neurotrophic factors with blood–brain barrier penetration and extensive Phase 1/2 safety data. • Enhances production of BDNF and GDNF, supporting neuronal survival and outgrowth. • Differentiated mechanism with broad potential to treat neurodegenerative disorders. • RT1999 completed Phase 2B development in Parkinson’s Disease. While the drug missed its primary endpoints, a subsequent post-hoc analysis suggested a significant slowing of the progression of motor symptoms. "The Raya CARES pipeline represents our conviction that ALS, PD and neurodegenerative diseases demand a multipronged therapeutic strategy," said Anjan Aralihalli, President & Founder of Raya Therapeutic. "In addition to advancing each compound for development in ALS and other neurodegenerative diseases, the company has identified synergistic combinations, which it will advance as subsequent life cycle management opportunities. Combination therapies will likely be necessary to fully treat heterogenous diseases such as ALS, PD and AD.” Members of the Raya management team will attend the 36th International Symposium on ALS/MND December 4-7th in San Diego, California. Members of the management team will also be available during the JP Morgan Annual Healthcare Conference January 12 – 15th, 2026 in San Francisco, California. The J.P. Morgan Healthcare Conference is the industry's leading global investment forum, bringing together international pharma and biotech companies as well as investors across the healthcare ecosystem. For more information about Raya and its innovative pipeline, visit www.rayatherapeutic.com About Raya Raya is a mission-driven company focused on the treatment of ALS, PD and other neurodegenerative diseases, leveraging the latest techniques for the selection and development of disease-modifying therapies. The company has a robust pipeline of five distinct clinical stage compounds that each target different pathways involved in motor neuron degeneration in ALS. The compounds were in-licensed following a rigorous selection process based on biological plausibility, clinical target engagement and functional clinical effects reflective of efficacy. This diversified approach enables the development of combination therapies, which may have a significant impact on disease progression. About Shionogi & Co., Ltd. Shionogi & Co., Ltd. is a leading global research-driven pharmaceutical company dedicated to bringing benefits to patients based on its corporate philosophy of "supplying the best possible medicine to protect the health and well-being of the patients we serve." Shionogi has discovered and developed novel antibiotics, medicines for HIV and influenza and currently markets medicines for infectious diseases and central nervous system disorders. Shionogi’s global pipeline includes research programs in infectious disease, pain/CNS, metabolic disorders, rare disease, oncology and stroke. For more information, please visit https://www.shionogi.com/global/en/ . About Kissei Pharmaceutical Co., Ltd. Kissei Pharmaceutical Co., Ltd. is a Japanese pharmaceutical company based on the management philosophy “contributing to society through high-quality, innovative pharmaceutical products” and “serving society through our employees.” As a strong R&D-oriented corporation, it concentrates on providing innovative pharmaceuticals to patients worldwide. Kissei Pharmaceutical Co., Ltd. is engaged in bringing new drugs into the world through drug discovery and licensing activities in its focus fields of rare/intractable diseases, urology, and nephrology/dialysis. For more information about Kissei Pharmaceutical Co., Ltd., please visit https://www.kissei.co.jp/e_contents/ . Anjan Aralihalli Raya Therapeutic, Inc. admin@rayatherapeutic.com Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.

临床2期上市批准临床3期临床结果

2025-06-03

·EINPresswire

Raya Therapeutic Announces Two Posters at the ENCALS Meeting in Turin, Italy June 3-6

Kim Staats, PhD., to present results of preclinical studies with RT1978 (Epertinib) and the combination of 2 NCEs with distinct mechanisms (RT1972 & RT1999). MONTREAL, QUEBEC, CANADA, June 3, 2025 / EINPresswire.com / -- Raya Therapeutic Inc. (“Raya”), a mission-driven company focused on the treatment of ALS and other neurodegenerative diseases, announces 2 poster presentations by Kim Staats, PhD., at the European Network to Cure ALS (ENCALS) Meeting June 3-6, 2025 in Turin, Italy. A poster entitled “Administration with RT1978 has protective effects across ALS preclinical models” will be presented by Dr. Staats on June 5th, which displays the protective effect of RT1978 in different models of ALS. This will include a survival extension in the SOD1-G93A mouse when treated with RT1978. Epertinib (RT1978), a blood-brain-barrier penetrating EGFR inhibitor, was originally discovered and developed by Shionogi & Co., Ltd., a leading pharmaceutical company based in Japan. This molecule has completed Phase 1/2 clinical development in another indication by Shionogi & Co., Ltd., and Raya is planning to develop it for ALS. A second poster entitled “The novel combination of 2 clinical-stage molecules demonstrates a beneficial effect in preclinical models of ALS” will also be presented by Dr. Staats on June 5th. This poster will display the additional benefits of co-administration of RT1972 and RT1999 in SOD1-G93A mice and primary neuronal cultures. Raya is developing these 3 novel small molecules (RT1978, RT1972 and RT1999), each of which are oral small molecules, cross the blood-brain-barrier, have been clinically tested in other indications, have favorable safety profiles, and are not yet approved for any indication. Raya aims to advance multiple drugs from its pipeline into clinical trials in 2026. This includes the clinical development of RT1978, RT1972 and RT1999 (the latter two compounds also as a combination). Members of the Raya management team will attend the ENCALS Meeting in Turin, Italy, June 3-6. https://www.encals.eu/meetings/encals-meeting-2025-turin-italy For more information about Raya and its innovative pipeline, visit www.rayatherapeutic.com About Raya Raya is a mission-driven company focused on the treatment of ALS, leveraging the latest techniques for the selection and development of disease-modifying therapies. The company has a robust pipeline of five distinct clinical stage compounds that each target different pathways involved in motor neuron degeneration seen in ALS patients. The compounds were in-licensed following a rigorous selection process based on biological plausibility, clinical target engagement and functional clinical effects reflective of efficacy. This diversified approach may enable the development of combination therapies which may have a significant impact on disease progression. To develop further combination therapies, Raya announced a strategic research collaboration with argenx on July 12, 2024: Link . This partnership explores synergistic effects of their combined drug candidates in the hope of developing more effective treatment options for ALS patients. Raya is further supported by global experts and will leverage a unique patient-friendly platform trial design offering new hope in the fight against ALS. About Shionogi & Co., Ltd. Shionogi & Co., Ltd. is a Japanese pharmaceutical company committed to discovering and developing novel medications to address global health challenges. Since its founding in 1878, Shionogi has been dedicated to improving patient lives through scientific innovation and collaboration. Contact Information for Media Inquiries: Anjan Aralihalli Raya Therapeutic, Inc. admin@rayatherapeutic.com Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the author above.

100 项与艾培替尼相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
乳腺癌	临床2期	法国	Shionogi & Co., Ltd.	2017-11-14
实体瘤	临床2期	欧洲	Shionogi & Co., Ltd.	2014-01-19
肿瘤	临床2期	-	Shionogi & Co., Ltd.	-
肌萎缩侧索硬化	临床前	加拿大	Raya Therapeutic, Inc.	2025-03-03
HER2阳性乳腺癌	临床前	日本	Shionogi & Co., Ltd.	2017-07-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AACR2017	临床1期	HER2阳性乳腺癌	-	S-222611	窪憲願積獵蓋願衊壓膚(顧夢範鹽窪選鑰鬱獵簾) = 積簾鹹獵願鹽膚憲顧鏇廠遞願壓遞蓋艱襯範鏇 (蓋醖鏇醖製蓋襯簾窪糧 ) 更多	-	2017-07-01
P4-21-08 (SABCS2017)	临床1/2期	HER2阳性乳腺癌 HER2+	45	S-222611 600mg	獵構簾選選壓廠製廠選(齋餘衊齋網積膚築壓蓋) = 鹽艱夢鑰蓋鏇鏇鬱構衊糧窪糧鏇鏇襯憲繭膚壓 (廠顧築鬱鬱夢壓壓積觸 ) 更多	积极	2017-02-15
P4-21-08 (SABCS2017)	临床1/2期	HER2阳性乳腺癌 HER2+	45	S-222611 200mg	獵構簾選選壓廠製廠選(齋餘衊齋網積膚築壓蓋) = 糧鑰顧鏇壓淵憲簾襯膚糧窪糧鏇鏇襯憲繭膚壓 (廠顧築鬱鬱夢壓壓積觸 ) 更多	积极	2017-02-15
P4-14-26 (SABCS2016)	临床1期	晚期恶性实体瘤 \| HER2阳性转移性乳腺癌 EGFR \| HER2-positive	76	S-222611 800 mg	繭鑰積艱獵鏇憲糧顧餘(鏇壓獵願鹹壓積製顧製) = most frequent adverse event 簾壓鏇醖願鹽衊簾鹹鬱 (簾憲窪簾醖廠醖夢窪築 ) 更多	积极	2016-02-15
ASCO2015	临床1期	晚期恶性实体瘤	76	S-222611 800mg	鹹夢構鏇製願獵積遞簾(齋製夢積遞遞艱壓壓糧) = 糧鹽構構願衊網選艱築築鹹衊顧遞窪衊遞襯憲 (網艱衊遞夢鹽壓窪餘鬱 ) 更多	-	2015-05-20