LY-2780301

Akt, also known as protein kinase B, is a crucial enzyme that plays a significant role in various cellular processes within the human body. It is a key mediator of cell survival, growth, and metabolism. Akt is involved in regulating multiple signaling pathways, including those related to cell proliferation, apoptosis, and glucose metabolism. It promotes cell survival by inhibiting apoptosis and stimulating cell growth and proliferation. Akt also regulates glucose metabolism by promoting glucose uptake and utilization. Dysregulation of Akt signaling has been implicated in various diseases, including cancer, diabetes, and neurodegenerative disorders. Understanding the role of Akt is essential for developing targeted therapies in the pharmaceutical industry. Basic research related to AKT has a relatively high academic starting point, with the earliest literature recorded in the top-tier journal "Proceedings of the National Academy of Sciences (PANS)". The prototype AKT gene was published in the journal Science in 1991. Due to the solid academic foundation established at the beginning, AKT has garnered attention in drug development from many pharmaceutical giants. Reviewing the development history of AKT drugs, the earliest companies involved in the exploration and clinical development of AKT inhibitors were pharmaceutical giants such as GlaxoSmithKline, Merck, Eli Lilly, Bayer, AstraZeneca, and Roche (Genentech). However, despite their well-known backgrounds, these companies have either sold off or terminated their AKT inhibitor developments, such as Eli Lilly's LY2780301 and Bayer's BAY1125976. This to some extent reflects the uncertainty of new drug development as well as the enormous complexity and challenges of the AKT signalling pathway. Merck's MK-2206 also ultimately failed after more than 40 early trials. Inherent or acquired drug resistance has always been the main reason why cancer drugs cannot maintain effectiveness, and eventually leads to treatment failure. Therefore, with the continuous exploration of potential mechanisms, discovering more promising drug targets has become the optimal treatment method for cancer treatment and prevention. The aberrant activation of the PI3K/AKT pathway and the transduction of its upstream or downstream targets play a crucial role as an important signalling pathway responsible for the resistance formation of various tumours. To enhance the sensitivity of tumour cells and combat tumour drug resistance, AKT inhibitors have also made some progress in clinical research. For example, in breast cancer, the PI3K/AKT pathway is considered a key player in the development of endocrine therapy resistance. The combined use of AKT inhibitors counteracts the activation of the PI3K/AKT pathway, thus exerting cytotoxic activity to prevent tumour cell resistance. Therefore, AstraZeneca and Roche are also evaluating the use of AKT inhibitors alone or in combination to develop new therapies for tumour treatment and to address treatment resistance.  How do they work?AKT inhibitors are a type of medication that target and inhibit the activity of the AKT The AKT , also known as protein kinase B, plays a crucial role in cell survival, growth, and proliferation. It is involved in various signaling pathways that regulate cell processes such as metabolism, apoptosis (cell death), and cell cycle progression. In the context of biomedicine, AKT inhibitors are of particular interest in cancer research and treatment. Dysregulation or overactivation of the AKT is commonly observed in many types of cancer, leading to uncontrolled cell growth and survival. By inhibiting the activity of the AKT , these inhibitors aim to disrupt the signaling pathways that promote cancer cell growth and induce cell death. AKT inhibitors can be developed as small molecules or targeted therapies, such as monoclonal antibodies or kinase inhibitors. They work by binding to specific regions of the AKT protein, preventing its activation or downstream signaling cascades. These inhibitors have shown promise in preclinical and clinical studies as potential anticancer agents, either as standalone treatments or in combination with other therapies. It is important to note that the use of AKT inhibitors may have potential side effects and limitations. Since AKT is involved in various cellular processes, inhibiting its activity can affect normal cell functions as well. Therefore, careful evaluation of the therapeutic benefits and risks is necessary when considering the use of AKT inhibitors in clinical settings. List of Akt InhibitorsThe currently marketed Akt inhibitors include: CapivasertibAfuresertibDordaviproneHonokiolIpatasertib DihydrochloridePerifosineSR-0379AntroquinonolCLR-131HC0201For more information, please click on the image below. What are Akt inhibitors used for?Akt inhibitors are being studied for the treatment of multiple diseases, including ovarian, prostate, breast, gastric, multiple myeloma, and melanoma. For more information, please click on the image below to log in and search. How to obtain the latest development progress of Akt inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of Akt inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

近日，阿斯利康宣布其AKT抑制剂capivasertib的Ⅲ期临床研究CAPItello-291的结果：与氟维司群单药相比，capivasertib联用氟维司群能显著改善晚期HR+乳腺癌患者的无进展生存期（PFS），达到了主要研究终点。阿斯利康还表示，AKT抑制剂可能成为HR+乳腺癌内分泌治疗耐药的新选择。AKT即丝氨酸/苏氨酸蛋白激酶（serine/threonine kinase），在细胞生长和增殖、凋亡抑制和血管生成的传导机制中发挥关键作用，是PI3K/AKT/mTOR信号通路的关键分子。目前全球尚无AKT抑制剂上市，仅有3款产品进入关键临床研究阶段（含临床III期及注册临床II期）：除已获得积极数据的capivasertib，还有罗氏的ipatasertib（GDC-0068），以及本土“黑马”来凯医药的afuresertib（LAE002）。这三款产品构成全球AKT研发的第一梯队，谁有机会率先终点冲线，且拭目以待。HR+乳腺癌耐药新策略HR+（激素受体阳性）/ HER2-（人表皮生长因子受体2阴性）是乳腺癌的最常见亚型，约占乳腺癌患者总数的70%。各国指南推荐该类患者的治疗方案包括内分泌疗法和CDK4/6抑制剂，而许多晚期乳腺癌患者在治疗后会产生耐药性，治疗选择有限。阿斯利康的capivasertib在HR+/HER2-乳腺癌领域，瞄准的是经内分泌疗法和CDK4/6抑制剂治疗耐药后的患者群体。Ⅲ期临床试验CAPItello-291招募的全部为接受内分泌联合或不联合CDK4/6抑制剂治疗期间或之后发生疾病复发或进展的乳腺癌患者，其中约40%的患者发生PIK3CA/AKT1/PTEN突变。该试验共纳入708例患者，评估capivasertib联合氟维司群对比安慰剂联用氟维司群治疗HR+/HER2-乳腺癌患者的疗效和安全性。结果显示，在主要疗效终点——总体人群和携带PIK3CA/AKT1/PTEN基因突变患者亚组的无进展生存期中，capivasertib联合氟维司群组都达到了疗效终点，PFS均具有统计学意义和临床意义的改善。次要终点总生存期（OS）数据尚不成熟。阿斯利康的成功无疑给整个AKT抑制剂研发领域增加了信心。国内企业来凯医药也布局了HR+/HER2-乳腺癌的开发。其核心产品afuresertib联合氟维司群治疗HR+/HER2-乳腺癌的全球多中心Ⅰb/Ⅲ期临床研究已经启动，今年5月，来凯宣布该临床研究完成受试者入组及首例给药。2018年，来凯从诺华引进afuresertib，获得该药的全球独家开发、生产及商业化权益。在国内，其他正在开发的AKT产品还有正大天晴的NTQ1062、海昶生物的WGI-0301，这两款产品正在开展治疗实体瘤的Ⅰ期临床。珍宝岛药业的HZB0071和浙江大学的Hu7691分别在2018年和2020年获得IND批准，但后续未见有进一步临床进展。多类肿瘤耐药性与AKT过表达相关除了HR+/HER2-乳腺癌，研发客还观察到AKT抑制剂在多个肿瘤领域均有临床研究开展。这与AKT靶点机制有很大关系。研究显示，卵巢癌、前列腺癌、乳腺癌等肿瘤的耐药性与AKT的过度表达高度相关。约40%的卵巢癌和乳腺癌，以及超过50%的前列腺癌中，均表现出AKT1激酶活性增加；近80%的激活AKT1的肿瘤为高分级和Ⅲ/Ⅳ期癌。约40%的卵巢癌中表现出AKT2激酶的活性。在雌激素受体缺陷型乳腺癌和雄激素不敏感的前列腺癌细胞系中，AKT3活性升高。来凯医药选择卵巢癌作为afuresertib的首个开发适应症，正在开展afuresertib联合紫杉醇针对铂耐药卵巢癌的全球多中心Ⅱ期注册临床研究（PROFECTA-Ⅱ）。目前卵巢癌的治疗手段主要是铂类为基础的化疗联合或不联合贝伐珠单抗或PARP抑制剂，但仍有超过80%患者的初始治疗后复发并产生耐药性，耐药后治疗方案有限。第一次复发患者中约25%为铂耐药性复发性卵巢癌（PROC），几乎所有复发性卵巢癌（ROC）患者最终都会产生铂耐药。根据先前诺华公开的数据，afuresertib已在临床前研究中证实其在PROC细胞系中恢复铂/紫杉醇敏感性的能力。已完成的Ⅰb期研究中，afuresertib在PROC患者中显示出潜在的抗肿瘤疗效，总缓解率（ORR）为32%，无进展生存期（PFS）达到7.1个月。在前列腺癌这一适应症上，阿斯利康、罗氏、来凯医药这三家公司都有布局。阿斯利康发起的一项Ⅱ期治疗转移性去势抵抗性前列腺癌（mCRPC）的临床试验ProCAID表明，capivasertib联合化疗治疗组的中位总生存期明显长于化疗对照组（31.2个月对照20.3个月）。来凯医药则将afuresertib与CYP17A1/CYP11B2双靶点抑制剂LAE001联用，探索对前列腺癌患者的二至四线治疗潜力，正在Ⅱ期研究中。罗氏的IPATunity150试验也取得部分成功，在携带PTEN缺失的mCRPC患者中，ipatasertib联合阿比特龙和泼尼松相比安慰剂组，能显著提高患者的放射学无进展生存期（rPFS）。但在总体人群中，ipatasertib未达到研究终点。除了肿瘤适应症，还有部分公司探索到了罕见病和皮肤疾病领域。例如Vaderis Therapeutics开发的VAD044，正在开展遗传性出血性毛细血管扩张症（HHT）的Ⅰ期临床研究。有研究发现，在HHT模型中过度激活PI3K-AKT信号通路，可以抑制血管过度扩张，减少动静脉畸形（AVM）形成，以缓解HHT的症状。DermBiont公司还开发了一款AKT外用制剂SM-020，治疗脂溢性角化病，处于Ⅱ期临床研究中。失败中探索AKT抑制剂的研发之路并非一帆风顺。比如，默沙东的MK-2206、礼来的LY2780301即折戟在研发早期阶段。罗氏的ipatasertib的两项乳腺癌Ⅲ期临床试验Ipatunity-130和Ipatunity-170在2021年相继终止。其中，Ipatunity-130是评估ipatasertib联合紫杉醇一线治疗PIK3CA/AKT1/PTEN突变TNBC或HR+/HER2-乳腺癌的疗效和安全性的研究，Ipatunity-170是ipatasertib联合阿替利珠单抗和紫杉醇一线治疗晚期三阴性乳腺癌（TNBC）的研究。研发客研究院观察到一个有趣的现象，虽然罗氏两项试验均在一线治疗上失败，但阿斯利康CAPItello-291研究瞄准的是现有治疗手段耐药后的二线患者群体，招募患者中约40%存在PIK3CA/AKT1/PTEN突变，来凯afuresertib对标的也是现有标准治疗耐药的患者。这不由得让人猜想：耐药后AKT过表达或许才是开启该领域的“钥匙”。不过，新药研发之路变幻莫测，阿斯利康CAPItello-291研究的成功是否与肿瘤耐药后AKT的过度表达有关，还有待更多的临床研究和试验数据去证实。总第1745期访问研发客网站可浏览更多文章www.PharmaDJ.com