Background:
Proteus syndrome is a rare overgrowth disorder. Most people begin to have symptoms between 6 months and 2 years of age. There are very few living adults with this disease. There is also no known treatment for it. Researchers want to see if a new drug can slow down or stop overgrowth in people with Proteus syndrome.
Objective:
To learn if miransertib is a safe and effective treatment for Proteus syndrome.
Eligibility:
People ages 3 and older with Proteus syndrome.
Design:
Participants will be screened with a medical checkup. They will answer questions about their medical history and current health. They will have a physical exam with vital signs. They will have an electrocardiogram to measure their heartbeat. They will give blood and urine samples. They will repeat the screening tests during the study.
Participants will take a miransertib pill once a day. They will bring their empty pill bottles with them to the NIH when they visit. If they can t swallow a pill, researchers will try to find other ways for them to take the drug.
Participants will have X-rays, ultrasounds, and imaging scans. Photos may be taken of their feet and other parts of the body that have or develop signs of Proteus syndrome.
Participants will have lung function tests to measure how much and how fast air moves out of their lungs.
Participants will complete surveys about their levels of pain, physical functioning, and quality of life.
Participants may have additional tests performed to assess their individual disease. They may have consultations with other specialists.
Participation lasts about 4 years. Participants will have 20-30 visits at the NIH.

开始日期2022-05-20

申办/合作机构

National Human Genome Research Institute

NCT04980872

/ Active, not recruiting临床2期

A Multicenter, Open-label, Phase 2, Extension Trial to Study the Long-term Safety in Participants With PROS or Proteus Syndrome Who Are Currently Being Treated With Miransertib in Other Studies

This is a study of the safety and tolerability of oral miransertib (MK-7075) administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS) or Proteus Syndrome (PS). This is an extension of other miransertib studies (MK-7075-002 [NCT03094832] or ArQule CU/EAP [NCT03317366]), and may also enroll participants who are approved for MK-7075-002 but have not yet started miransertib therapy.

开始日期2021-11-02

申办/合作机构

Merck Sharp & Dohme Corp.

NCT03094832

/ Terminated临床1/2期

A Phase 1/2 Study of ARQ 092 (Miransertib) in Subjects With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome

This is an open label, Phase 1/2 study of oral miransertib (MK-7075) administered to participants at least 2 years of age with phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)-related Overgrowth Spectrum (PROS) and Proteus Syndrome (PS) (MOSAIC).

开始日期2017-05-16

申办/合作机构

ArQule, Inc.

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100 项与 Miransertib 相关的临床结果

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100 项与 Miransertib 相关的转化医学

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100 项与 Miransertib 相关的专利（医药）

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项与 Miransertib 相关的文献（医药）

2025-08-01·COMPUTATIONAL BIOLOGY AND CHEMISTRY

A computational journey in anticancer drug discovery: Exploring AKT1 inhibition by novel oxadiazoles using molecular docking, ADMET, density functional theory and molecular dynamic simulation

Article

作者: Kumar, Shubham ; Sharma, Vishnu ; Paradkar, Omkar ; Naik, Gauri Alias Pooja ; Wadhwa, Pankaj ; Gupta, Pawan

AKT, also called (PKB) Protein Kinase B, is critical for cell proliferation, metabolism, and survival, with its dysfunction linked to various diseases, including cancer. The oxadiazole nucleus has demonstrated significant anticancer activity in literature surveys. The motivation for conducting this study stems from the fact that, despite numerous investigations into novel therapeutic targets and lead compounds, the inhibition of AKT1 presents limited treatment options due to various adverse drug reactions and specificity issues, given that AKT1 exists in three isoforms. So, this study aimed to identify top-hit molecules with 1,3,4 oxadiazole scaffold targeting the AKT1 enzyme by ligand-based virtual screening to produce a dataset library from PubChem database, structure-based virtual screening followed by ADMET profiling, DFT, and molecular dynamic simulation study as an innovative approach, as there is a dearth of AKT1 inhibitors that comprise oxadiazole in the market and clinical trials. The study employs a combination of advanced computational methods, including virtual screening, molecular docking, molecular dynamics simulations, density functional theory calculations, and ADMET predictions. This comprehensive approach offers a thorough investigation of prospective drug candidates. A comprehensive pharmacoinformatic analysis was conducted on a library of compounds containing oxadiazole rings. A total of 1000 compounds were analyzed through virtual screening utilizing molecular docking and subsequent validation, aiming to identify inhibitors that exhibit a strong affinity for binding for AKT1 (PDB ID: 3O96). Thus, 24 compounds demonstrating binding affinities analogous to the standard emerged as the most promising medicinal prospects and underwent ADMET profiling, and DFT studies followed by a molecular dynamic study on the best 2 compounds. Moreover, these compounds found by ADMET profiling showed suitable pharmacokinetic and pharmacodynamic profiles and were non-toxic using DFT analysis determining ideal structural characteristics. Especially showing comparable stability to the reference molecule over 200 ns in MD simulations, the best top 2 hit compounds having binding affinity -10.7 kcal/mol for PCOS_ 133 (CID-164189) and -11.6 kcal/mol for PCOS3_42 (CID-158973) emerged as potential AKT1 inhibitors for cancer therapy in comparison to -11.6 kcal/mol and -14.7 kcal/mol binding affinity of Miransertib reference drug and IQO cocrystallized ligand of AKT1 protein PDB code 3O96. LEU-210, LEU-264, ASP-292, and TRP-80 are the important amino acid residues required for AKT1 inhibition. These results provide important new perspectives for the rational design and optimization of oxadiazole-based AKT1/PKB inhibitors, therefore laying a strong basis for experimental validation including further in-vitro and in vivo studies and PKB inhibitor development.

2025-07-25·Orphanet Journal of Rare Diseases

Safety findings from the phase 1/2 MOSAIC study of miransertib for patients with PIK3CA-related overgrowth spectrum or Proteus syndrome.

Article

作者: Perkins, Jonathan ; Hammill, Adrienne ; Buonuomo, Paola Sabrina ; Leoni, Chiara ; Liaw, Danny ; Huang, Mo ; Iacobas, Ionela ; Simonetti, Alessandra ; Eng, Whitney ; Goldmacher, Gregory ; Briones, Michael ; Zampino, Giuseppe ; Goel, Himanshu

BACKGROUND:

PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome are associated with mosaic tissue overgrowth of varying severity that commonly presents in childhood. The multicenter, open-label, phase 1/2 MOSAIC study (NCT03094832) was designed to evaluate the clinical efficacy and safety of the selective pan-AKT inhibitor miransertib for participants with PROS or Proteus syndrome.

METHODS:

Participants ≥ 2 years of age with PROS with documented somatic PIK3CA mutations or Proteus syndrome with documented somatic AKT1 mutations were enrolled to receive oral miransertib at a starting dose of 15 mg/m² every day for the first 3 cycles (1 cycle = 28 days) and miransertib 25 mg/m² every day thereafter, provided no clinically significant drug-related toxicities were observed. The initial primary objective of the study was to assess clinical response to miransertib. Due to study design and data collection limitations, evaluating efficacy was no longer considered feasible and the primary objective was updated in 2021 to evaluate the safety and tolerability of miransertib.

RESULTS:

Between May 16, 2017 and January 25, 2021, 49 participants were enrolled and received ≥ 1 dose of study drug, comprising the safety analysis population. Forty-five participants had a diagnosis of PROS and four had a diagnosis of Proteus syndrome. The median (range) age at enrollment was 7 years (2-41). Median (range) duration of treatment was 20.5 months (9.9-45.6). A total of 23 (46.9%) participants had a drug-related adverse event, most commonly decreased neutrophil count (n = 6, 12.2%), increased blood insulin (n = 5, 10.2%), and stomatitis (n = 5, 10.2%). One (2.0%) participant experienced a grade 3 drug-related adverse event (deep vein thrombosis). No drug-related adverse events led to early study discontinuation or death. Laboratory assessment values remained generally stable throughout the study.

CONCLUSION:

Miransertib was safe and tolerable in participants with a confirmed diagnosis of PROS or Proteus syndrome. Future investigations are needed to determine whether patients receive measurable clinical benefit from miransertib.

TRIAL REGISTRATION:

NCT03094832 registered Mar 28, 2017, https://clinicaltrials.gov/ct2/show/NCT03094832 .

2025-04-01·MOLECULAR DIVERSITY

An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs

Article

作者: Etikyala, Umadevi ; Manga, Vijjulatha ; Dalimba, Udayakumar ; Reddyrajula, Rajkumar ; Kuchana, Vinutha ; Vani, T

Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R² and Q² values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1-D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein-ligand complex.

项与 Miransertib 相关的新闻（医药）

2024-12-10

·药精通Bio

【Nature】AKT 激酶共价赖氨酸(Lys)抑制剂

AKT1 激酶是 PI3K 激酶信号转导通路的关键效应器，该通路驱动细胞增殖并在多种肿瘤中异常激活。近期，Nature 杂志上发表了基于结构的药物设计来开发基于 Lys 共价抑制剂，选择性地针对致癌 AKT1 突变体，并避免泛 AKT 抑制剂的剂量限制毒性（10.1038/d41573-024-00197-y）。蛋白激酶AKT也被称作蛋白激酶B（protein kinase B，PKB），属于丝氨酸/苏氨酸蛋白激酶，同时也是致癌基因。AKT位于PI3K-AKT-mTOR信号通路（PAM）的中心节点。PAM整合细胞外和细胞内信号，在细胞代谢、生长、增殖中发挥核心调控作用。正常细胞中AKT自身抑制，在癌症中因突变而发生信号上调，从而驱动细胞增殖，是药物开发的重要靶点。 AKT已发现三种亚型：AKT1、AKT2、AKT3，具有80%以上的同源性，仅在PH结构域和激酶结构域连接处存在较大差异，但是它们在体内分布和生理功能上并非完全相同。因此在药物开发过程中需要选择性靶向AKT不同亚型。 AKT抑制剂按照结合位点不同，可以分为PH结构域抑制剂、变构抑制剂和ATP竞争性抑制剂。大多数 ATP 竞争性和变构抑制剂都以所有三种 AKT 旁系同源物为目标。例如2023 年上市的Capivasertib 属于ATP竞争性抑制剂，同时抑制AKT三种亚型，与Faslodex（氟维司群）联用，治疗HR+/HER2-的晚期或转移性乳腺癌成年患者。然而，广谱AKT抑制剂的毒性为高血糖，导致Capivasertib用药窗口窄，进一步可能导致对AKT1的抑制不足。小鼠和人类基因组研究显示，高血糖副作用归因于对AKT2的抑制。加州大学研究人员开始寻找专门针对最常见的 AKT1 癌蛋白的抑制剂，特别是其中赖氨酸突变了的 PH 结构域中的 Glu17 (E17K)，从而导致组成型激酶激活。研究报道，AKT(E17K)的在肿瘤中突变率分别为乳腺癌 (8%，5/61) 、结肠直肠癌中 (6%,3/51) 和卵巢癌 (2%，5/50) 。为了共价结合突变体 Lys17，作者首先模拟了该残基对与变构抑制剂 (ARQ092) 结合的野生型 AKT1 晶体结构的影响，变构抑制剂占据 PH 和激酶结构域之间的口袋。该模型表明，Lys17 的反应性 ε-胺基团可能会被从结合在变构袋的基于 ARQ092 的支架延伸出来的亲电水杨醛基团(salicylaldehyde)捕获。 AKT 别构抑制剂ARQ092 基于这一策略，作者合成了一系列共价抑制剂，它们在体外和细胞内选择性结合 AKT1 (E17K) 而不是 AKT2 和野生型 AKT1。结合是可逆的，并且 Lys17 被质谱证实是主要的共价修饰位点，而不是 AKT 旁系同源物中保守的附近赖氨酸残基。与表达 WT AKT1 的细胞系（SKBR3）相比，优化的抑制剂“化合物 4”可诱导表达 AKT1 (E17K) (LAPC4-CR)的前列腺癌细胞系更有效的细胞杀伤。在携带表达 AKT1 (E17K) 的异种移植肿瘤的小鼠模型中，每天两次腹膜内施用化合物 4，持续三周，可抑制肿瘤生长；它在表达野生型 AKT1 的异种移植模型中效果较差。重要的是，化合物 4 不影响血糖，而 ARQ092 则会明显诱导高血糖。与抑制剂结合的 AKT1 (E17K) 的晶体结构鉴定出 Lys17 和水杨醛部分之间的亚胺键，并揭示该复合物通过与亚胺缀合物和激酶结构域中的两个半胱氨酸结合的内源 Zn 2+离子进一步稳定。总体来说，开发赖氨酸靶向共价抑制剂一直具有挑战性，作者提出，他们使用水杨醛部分并通过两个近端残基招募 Zn 2+的策略可以应用于其他靶点。这项研究报告了针对突变癌蛋白 AKT1 (E17K) 的共价抑制剂，由于极长的停留时间，其选择性优于 WT AKT 旁系同源物。E17K 改变持续激活 AKT1 激酶信号传导，并已在多种实体瘤类型中得到鉴定。尽管泛 AKT 抑制剂在 AKT1 (E17K) 突变肿瘤的一部分患者中显示出令人鼓舞的初步活性，但靶向毒性（例如高血糖）需要间歇和/或减少剂量，这可能会导致AKT1 (E17K) 接合度不理想。通过为靶向共价抑制剂创建独特的亲核试剂，E17K 改变提供了持续激酶抑制的潜力，并提高了相对 WT AKT 旁系同源物的选择性。然而，这一机遇伴随着赖氨酸靶向共价抑制剂的开发所固有的重大挑战，包括亲核性大大降低以及赖氨酸相对于半胱氨酸的普遍性更高。在这里，作者报告了“新型锌螯合物”的形成，该螯合物包含可逆共价抑制剂和不与 Zn 2+结合的蛋白质。此前有报道，一类非共价抑制剂可通过螯合增强结合，将外来 Zn 2+募集至胰蛋白酶样丝氨酸蛋白酶的催化位点。最近，内源性 Zn 2+螯合与乳酸与 SUMO 水解酶 SENP1 的结合有关，而 SUMO 水解酶 SENP1 不会与过渡金属结合。原则上，水杨醛部分的赖氨酸修饰与两个近端侧链（例如 Cys 或 His）招募 Zn 2+偶联的配体设计策略可以应用于除 AKT1 (E17K) 之外的其他蛋白质靶标，从而增强效力和选择性。该策略还可用于靶向功能性金属结合位点附近的赖氨酸，例如金属酶或什至结构或调节域（例如锌指），其中金属结合本质上较弱或受到致病突变的损害。锌离子、非共价抑制剂与蛋白酶（10.1038/35422）乳酸与 SENP1 活性位点的锌形成复合物，抑制 APC4 去 SUMO 化（10.1038/s41586-023-05939-3）。尽管需要进一步优化来开发口服生物可利用的 AKT1 (E17K) 水杨醛抑制剂，但最近批准的基于水杨醛的药物 voxelotor（其靶向血红蛋白的氨基末端胺）表明这是一个可以实现的目标。尽管存在这些挑战，该研究证明了共价靶向突变致癌赖氨酸并抑制 AKT1 (E17K) 驱动的恶性肿瘤生长而不抑制 AKT2 或诱导高血糖的可行性。 END 免责声明：本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 OTC2024类器官前沿应用与3D细胞培养论坛圆满落幕，点击图片可查看会后报告，咨询OTC2025类器官论坛请联系：王晨 180 1628 8769

2023-04-27

·FierceBiotech

Merck reveals HIV combo trial is back in the running after FDA partial hold lifted

Merck executives said on a first-quarter earnings call that the company is restarting a phase 2 trial testing a combination of islatravir and Gilead’s lenacapavir. The middle of Merck & Co.’s clinical batting order took center stage on the company’s first-quarter earnings call, including a phase 2 HIV combo therapy that once again returned to the lineup. The Big Pharma has resumed a phase 2 study of MK-8591D, an oral regimen of islatravir and Gilead’s Sunlenca, executives said on a call with analysts Thursday. Gilead's drug was approved in December as a twice-yearly treatment for patients with multi-drug resistant HIV. The two companies decided to slam the brakes on the trial back in November 2021 after dosing was stopped in a related study testing a combo of islatravir and another drug called MK-8507. At the time, Merck disclosed that the islatravir-MK-8507 combo spurred a reduction in patients’ lymphocyte and CD4+ T-cell levels. But now islatravir is being revived, with an FDA hold on the trial having been lifted after an amended protocol using a lower dose of islatravir was agreed to, according to a Merck spokesperson. In addition, the company is launching multiple new phase 3 studies testing the med with its FDA-approved HIV drug Pifeltro. “We are committed to advancing the science to offer new treatment options for the treatment of HIV,” Dean Li, M.D., Ph.D., president of Merck Research Labs, said on the call. But elsewhere the company is reevaluating priorities. A spokesperson confirmed to Fierce Biotech that MK-7075, a treatment for overgrowth syndrome that did not appear in the company's earnings presentation, is "not currently active." The med is still in development but is being deprioritized, the spokesperson explained. The mid-stage pipeline updates come as Merck’s executives touted internal and external victories meant to assure investors that its post-Keytruda plans were materializing. Less than two weeks ago, the company announced it was buying Prometheus Biosciences for $10.8 billion, an immunology company with a promising lead asset developed to treat ulcerative colitis and Crone’s disease that recently posted a phase 2 victory. That med, PRA023, is set to do battle with a competitor from Roivant that's so far performed similarly. The deal echoes Merck’s $11.5 billion acquisition of Acceleron Pharma in September 2021, which handed the New Jersey pharma keys to cardiovascular med sotatercept, now a potential crown jewel. After diving deeper into the med’s phase 3 victory, Merck executives said today that they plan to file for U.S. approval in the third quarter for patients with pulmonary arterial hypertension. Chief Medical Officer Eliav Barr, M.D., previously told Fierce Biotech that he expects the drug to launch in early 2024. The sum of the Big Pharma’s recent deals and internal development had CEO Rob Davis sounding confident that Merck is well-situated to thrive beyond Keytruda’s expected loss of exclusivity in 2028. “I am no longer focusing on 2028,” he said on the call. “I am looking at 'how do we have sustainable growth well into the next decade.'"

临床2期并购临床3期上市批准

2022-10-26

·BiG生物创新社

金坚团队：首个靶向AKT变构位点的PROTAC

西奈山伊坎医学院金坚教授团队长期深耕于靶向蛋白降解领域，致力于蛋白降解药物的设计与开发，以及推进这些技术的临床应用与转化。该团队已经成功开发了多种靶点的PROTAC，克服了传统小分子药物的种种缺陷，为靶向蛋白降解领域的研发不断注入强心剂。包括：组蛋白甲基转移酶NSD家族NSD2/3，激酶家族AKT和ALK，EGFR以及表观遗传家族靶点EZH2等。此外，金坚教授团队也开发了其他新型PROTAC技术：1、叶酸笼罩的Folate-Caged PROTACs，该类PROTAC进一步提高了PROTAC的细胞选择性。2、基于寡核苷酸链的TF-PROTACs，成功实现了对不可成药转录因子的降解。3、光诱导PROTACopto-PROTAC，实现了PROTAC的可控激活。4、靶向WDR5 和Ikaros的双靶点PROTAC5、开发新型的E3连接酶KEAP1配体，并成功用于BRD3/4的降解。进一步拓展了靶向蛋白质降解的有限工具箱。前言AKT是癌症治疗的一个重要靶点。近年来，在开发ATP竞争性的活性位点和变构位点的AKT抑制剂方面取得了重大进展，多款AKT小分子抑制剂获批临床。此外，研究人员也开发了多种基于AKT活性位点的PROTAC，包括MS21。MS21可以有效诱导PI3K/pten通路突变的肿瘤细胞中AKT的降解，并有效抑制肿瘤细胞增殖生长，但在KRAS/BRAF突变细胞中却显得束手无策，无法降解AKT蛋白。近日，西奈山伊坎医学院金坚教授团队和Ramon E. Parsons团队在知名药物化学期刊JMC上发表题为“Novel Allosteric Inhibitor-Derived AKT Proteolysis Targeting Chimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells”的文章。作者开发了首个基于变构位点的新型AKT PROTAC 62，并且化合物62在KRAS/BRAF突变的癌细胞以及PI3k/pten突变的癌细胞中均显示出强效的AKT降解活性和抗增殖活性。此外，62在通过腹腔内给药的小鼠体内表现出良好的生物利用度和PK性质。作者 | 缪可研AKT靶点介绍AKT（蛋白激酶b）是一种丝氨酸/苏氨酸激酶，属于丝氨酸蛋白激酶家族。AKT作为人类癌症中最常见的PI3K/AKT/m-TOR信号级联的中心节点，在调节癌症特征中发挥关键作用，如细胞增殖、代谢、转移、侵袭性和肿瘤细胞的存活（图1）。AKT由三个高度同源的亚型组成，AKT1/2/3，它们都有三个进化上保守的结构域：一个N端PH结构域，一个中心激酶催化结构域和一个C端调控结构域。研究表明，AKT的过度活化和过表达与许多总体预后较差的人类癌症有关。图1.AKT介导的信号通路AKT小分子抑制剂研究进展AKT是一种极具临床潜力的药物靶点。在过去数十年来，基于AKT领域的药物研发已经取得了积极的研究成果，多款AKT小分子抑制剂相继获批临床，包括靶向AKT活性位点的小分子抑制剂：GSK690693、GDC-0068、AZD5363和靶向AKT变构位点的抑制剂：MK-2206、ARQ-092、TAS-117。进展最快的是罗氏的GDC-0068和阿斯利康的AZD5363，目前均处于临床三期。然而，基于活性位点的AKT抑制剂具有严重的副作用，包括高血糖、血小板减少和感染，而AKT变构抑制剂在人体临床试验中也表现出有限的疗效。图2.进入临床试验的AKT小分子抑制剂已报道的基于活性位点抑制剂的AKT PROTAC基于靶向蛋白水解嵌合体PROTAC或分子胶的靶向蛋白降解技术（TPD）是一种通过降解致病靶蛋白来治疗疾病的治疗策略。通常，由PROTAC或分子胶诱导的泛素−蛋白酶体系统（UPS）介导的降解可以同时靶向癌蛋白的催化和非催化结构域，这可能产生比小分子激酶抑制剂更大的疗效。近年来，研究人员已经开发了多种靶向活性位点的AKT PROTAC（图3），其中，MS21是已报道最有效的AKT降解剂，然而MS21不能有效诱导携带KRAS或BRAF突变的癌细胞中AKT的降解。为了克服MS21等靶向活性位点PROTAC在携带KRAS/BRAF突变的癌细胞较差的降解AKT能力。作者另辟蹊径，试图从AKT的变构抑制剂切入，开发新型的靶向变构位点的AKT降解剂。图3.已报道的靶向活性位点的AKT PROTAC下面让我们一起走进这篇文献：1. 基于ARQ-092 PROTAC的设计思路及合成研究表明，与ATP竞争性结合的AKT活性位点抑制剂优先结合激活的AKT（磷酸化的AKT，p-AKT）。由于在KRAS/BRAF突变的肿瘤细胞系中，磷酸化AKT蛋白水平较低，这就影响了与ATP竞争性结合的活性位点抑制剂的效果，从而导致耐药。与靶向活性位点抑制剂不同，AKT变构抑制剂可以结合并稳定AKT的失活形式。因此，靶向AKT变构位点的PROTAC有可能在含有KRAS/BRAF突变的癌细胞中参与结合失活的AKT，这就可能诱导MS21耐药肿瘤细胞系中AKT的降解。首先，作者选取了AKT变构抑制剂ARQ-092作为AKT PROTAC的靶头化合物，随后通过对ARQ-092与AKT1的晶体复合物进行分析，作者发现ARQ-092中的左侧苯环伸向溶剂区（图4）。因此，作者选用该位点作为连接位点进行衍生化，分别合成了末端是羧基和氨基的化合物1（末端羧基）和2（末端氨基）。随后，作者基于化合物1和2开展PROTAC合成工作。图4. ARQ-092与AKT1的晶体复合物及化合物1和2的化学结构VHL配体VHL-1和CRBN配体泊马度胺是最常用的两种E3泛素连接酶配体。作者同时采用这两种E3配体，分别合成了基于VHL配体和CRBN配体两种类型的AKT PROTAC。最先开展的是基于化合物1（末端羧基）的PROTAC合成（图5）。其中，化合物3-20是基于VHL配体的PROTAC，作者分别合成了不同长度的聚乙二醇和烷烃链两种类型PROTAC。同时作者也合成了基于泊马度胺的PROTAC 21-32，同样采用了不同长度的聚乙二醇和烷烃链两种连接链类型。图5.基于化合物1的AKT PROTAC接下来，作者合成了基于化合物2（末端氨基）PROTAC 33-61（图6）。其中，化合物33-49是基于VHL配体的PROTAC，化合物50-61是基于泊马度胺的PROTAC。并且作者同样也考察了不同长度的聚乙二醇和烷烃链的连接链类型，其中化合物33-41和57-61是聚乙二醇类型的PROTAC，化合物42-49和50-56是烷烃链类型的PROTAC。图6.基于化合物2的AKT PROTAC2. PROTAC蛋白降解能力初筛实验接下来，作者在PC3细胞系（人前列腺癌细胞）上筛选合成的PROTAC 3-61对AKT蛋白的降解能力（图7）。蛋白降解实验表明基于VHL配体的PROTAC比基于泊马度胺的PROTAC具有更强的降解能力，且烷烃链比聚乙二醇链更有效。作者从构效关系研究发现了PROTAC 20、48和49具有较强的AKT降解能力，并可以有效抑制下游信号传导，如：p-akt、p-pras40和p-s6。图7. 化合物3-61的蛋白降解实验3. 基于最优化合物20的进一步结构优化及后续生物活性研究有研究表明，VHL-2（VHL-1中苄位甲基取代的结构）对VHL具有更高的亲和力。因此，作者选用了降解活性最好的PROTAC 20进行进一步结构改造，将20中的VHL-1替换成具有更高亲和力的VHL-2，得到了PROTAC 62。作者也分别合成了化合物63和64作为阴性对照化合物（图8）。图8. PROTAC 62及阴性对照63和64的化学结构首先，作者分别测试了PROTAC 62、63、64及靶头化合物ARQ-092对AKT三种不同亚型（AKT1、AKT2、AKT3）的酶抑制活性（图9）。实验结果显示，相较于靶头化合物ARQ-092，PROTAC表现出减弱的抑制活性，但对于AKT1/2/3都具有抑制活性。图9. PROTAC 62、63、64及ARQ-092的酶活测试接下来，作者测试了PROTAC 62、63、64在MS21（已报道的降解活性最好的靶向活性位点PROTAC）耐药且KRAS突变的结直肠癌细胞系SW620的降解活性（图10）。实验结果表明，化合物62能够呈现浓度依赖方式有效诱导SW620中的AKT降解，且DC50为23±16 nM，而阴性对照63和64无降解活性。图10.化合物62在sw620中的降解实验随后，作者比较了62和MS21在其他几种携带KRAS或BRAF突变的癌细胞类型中的AKT降解效应（图11）。蛋白质印迹实验发现，化合物62可以有效诱导各种KRAS或BRAF突变的癌细胞中AKT的降解，而MS21表现出较差的AKT降解能力。图11. 62和MS21在各种携带KRAS或BRAF突变的癌细胞蛋白降解实验作者继续在SW620细胞系进行了蛋白降解机制研究（图12），实验结果表明化合物62可以以时间依赖的方式诱导AKT降解，并可以有效抑制磷酸化PRAS40蛋白水平。当加入NAE抑制剂MLN4924或蛋白酶体抑制剂MG132后，可以有效逆转AKT的降解效果。基于上述实验结果，作者认为化合物62诱导AKT蛋白的降解效果依赖于泛素蛋白酶体途径。图12. 蛋白降解机制研究实验为了探究PROTAC 62蛋白质组范围内的降解选择性，作者对化合物62进行了基于全局串联质谱标签TMT定量蛋白分析的蛋白质组学研究，实验结果表明化合物62不能降解其他靶点蛋白，具有较好的靶点选择性（图13）。图13.化合物62的蛋白质组学研究接下来，作者在SW620细胞系上测试了化合物62、靶头化合物ARQ-092、阴性对照64及降解剂MS21的抗增殖活性（图14）。从细胞集落形成实验可以看出，化合物62对SW620抑制活性与ARQ-092相当，而阴性对照化合物64和MS21表现出较弱抑制活性。图14. 化合物62、64、ARQ-092、MS21的细胞集落形成实验最后，作者对化合物62进行了PK研究（图14），评估化合物62在小鼠体内的生物利用度。实验结果发现在给药后0.5 h可达到最大血药浓度（Cmax = 1 μM），血药浓度保持在100 nM以上至少可维持12小时。这些结果表明，化合物62表现出较好的PK性质，在体内可以获得足够的血浆暴露。图14. 化合物62在小鼠血浆浓度测试总结金坚课题组报道了首个靶向变构位点的AKT PROTAC 62，PRORAC 62能够有效诱导KRAS/BRAF突变肿瘤细胞的AKT降解，这可能为靶向活性位点的MS21耐药KRAS/BRAF突变癌症提供一个潜在的策略。同时，化合物62表现出较强的降解活性、较好的靶点选择性以及较好的PK性质，这是靶向AKT PROTAC领域的一大步，也是靶向AKT领域的药物研发的一大步。参考文献1、Novel Allosteric Inhibitor-Derived AKT Proteolysis TargetingChimeras (PROTACs) Enable Potent and Selective AKT Degradation in KRAS/BRAF Mutant Cells.2、Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discovery 2005, 4 (12), 988−1004.3、Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation. DOI: 10.1021/jacs.1c04841. J. Am. Chem. Soc.2021, 143, 37, 15073–150834、4、TF-PROTACs Enable Targeted Degradation of Transcription Factors.J. Am. Chem. Soc.2021, 143, 23, 8902–8910. doi.org/10.1021/jacs.1c03852扫码加入BiG生物创新社读者交流群，分享、交流纯粹的行业知识，非诚勿扰！BiGScientific Driven, Making Impact!创新生态丨医药论坛丨行业分析媒体公关丨BiG Webinar联系我们商务：Max 18662346610媒体：Kathy 17621909690

蛋白降解靶向嵌合体小分子药物免疫疗法

100 项与 Miransertib 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D11409	-	-	DB14982

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适应症	最高研发状态	国家/地区	公司	日期
生长障碍	临床2期	西班牙	Merck GmbH	2019-09-19
PIK3CA相关的过度生长现象	临床2期	西班牙	ArQule, Inc.	2017-05-16
Proteus综合征	临床2期	西班牙	ArQule, Inc.	2017-05-16
子宫内膜癌	临床1期	美国	ArQule, Inc.	2015-06-09
卵巢癌	临床1期	美国	ArQule, Inc.	2015-06-09
局部晚期恶性实体瘤	临床1期	美国	ArQule, Inc.	2011-11-01
复发性淋巴瘤	临床1期	美国	ArQule, Inc.	2011-11-01
先天性心脏缺损	临床前	美国	Merck GmbH	-
血管闭塞危机	临床前	美国	Merck GmbH	-

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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


NCT03094832 (MK-7075-002 \| 7075-002 \| MOSAIC, CTgov)	临床1/2期	PIK3CA相关的过度生长现象 \| Proteus综合征	50	Miransertib (Part A: Miransertib PROS/PS)	築廠觸鏇齋襯觸鹽淵網 = 膚繭築獵鬱繭蓋衊願醖觸壓糧顧獵遞窪獵憲壓 (糧顧範窪襯遞築簾構獵, 夢糧構醖鏇憲糧簾鹽築 ~ 遞鬱衊網衊簾淵範醖廠) 更多	-	2023-03-31
NCT03094832 (MK-7075-002 \| 7075-002 \| MOSAIC, CTgov)	临床1/2期	PIK3CA相关的过度生长现象 \| Proteus综合征	50	Miransertib (Part B: Miransertib PROS (Cohort 1))	築廠觸鏇齋襯觸鹽淵網 = 餘廠襯鹹鹽範製夢觸淵觸壓糧顧獵遞窪獵憲壓 (糧顧範窪襯遞築簾構獵, 簾築鹽築襯餘鬱簾築齋 ~ 範觸鹽構襯壓鏇壓獵襯) 更多	-	2023-03-31
NCT03094832 (MK-7075-002 \| 7075-002 \| MOSAIC, Biospace) 人工标引	临床1/2期	PIK3CA相关的过度生长现象 \| Proteus综合征	-	Miransertib	築遞積觸顧窪積淵顧醖(繭簾襯築淵獵壓廠壓壓) = mostly Grade 1 or 2 AEs 積鏇築積範構鬱鬱壓膚 (糧繭鏇壓願廠獵壓鹹製 ) 更多	积极	2019-06-17
NCT02594215 (Pubmed \| Adv Exp Med Biol) 人工标引	临床1期	Proteus综合征	6	Miransertib	衊糧鬱觸願鏇齋糧廠網(壓蓋膚窪鹹壓願襯構鬱) = 50% reduction (5/6) 餘衊夢繭顧糧積夢衊餘 (願廠淵糧簾醖簾獵選願 )	积极	2019-03-07
NCT02476955 (ASCO 12017 \| ASCO 22017) 人工标引	临床1期	实体瘤	13	carboplatin+paclitaxel+ARQ 092	鑰糧網選廠網糧艱願糧(範蓋鹽網構構齋餘顧壓) = diarrhea 69%, fatigue 54%, hyperglycemia 31%, maculopapular rash 31%, nausea 23%, mucosal inflammation 23%, anemia 15%, platelet count decreased 15% and hypokalemia 15% 淵積選廠遞廠繭壓艱齋 (觸鑰窪糧餘醖襯鬱衊築 ) 更多	积极	2017-06-05
AACR2013	临床1期	HR阳性/HER2低表达实体瘤	22	ARQ 092	憲鹽淵網窪鹽願壓築遞(遞鏇夢鏇窪鏇築憲遞餘) = 願廠廠鹽觸蓋齋遞積網餘構選鑰築構憲觸鹹窪 (構廠製鹹顧構齋築選製 )	-	2013-04-15