This study will evaluate the safety and tolerability of oral KPT-9274 for the treatment of patients with relapsed or refractory acute myeloid leukemia.

开始日期2021-08-27

申办/合作机构

University of Colorado Denver

[+1]

NCT04281420 / Terminated临床1期

A Phase I Open-Label Study of the Safety and Tolerability of ATG-019, a Dual Inhibitor of PAK4 and NAMPT, in Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma

This is a multi-center, open-label clinical study with separate Dose Escalation and Expansion Phases to assess preliminary safety, tolerability, and efficacy of ATG-019, a dual inhibitor of PAK4 and NAMPT, alone or co-administered with starting dose of 500 mg niacin ER in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL).

开始日期2020-04-13

申办/合作机构

德琪医药有限公司

100 项与 KPT-9274 相关的临床结果

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100 项与 KPT-9274 相关的转化医学

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100 项与 KPT-9274 相关的专利（医药）

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项与 KPT-9274 相关的文献（医药）

2023-12-01·Molecular cancer therapeutics

Anticancer Efficacy of KRASG12C Inhibitors Is Potentiated by PAK4 Inhibitor KPT9274 in Preclinical Models of KRASG12C-Mutant Pancreatic and Lung Cancers

Article

作者: Bannoura, Sahar F ; Beal, Eliza W ; Aboukameel, Amro ; Beydoun, Rafic ; Azmi, Asfar S ; Tobon, Miguel E ; Shields, Anthony F ; Azar, Ibrahim ; Alkhalili, Osama ; Mzannar, Yousef ; Philip, Philip A ; Senapedis, William ; Kim, Steve H ; Al Hallak, Mohammed Najeeb ; El-Rayes, Bassel F ; Nagasaka, Misako ; Khan, Husain Yar ; Mohammad, Ramzi M ; Baloglu, Erkan ; Uddin, Md Hafiz

Abstract:

KRASG12C inhibitors, such as sotorasib and adagrasib, have revolutionized cancer treatment for patients with KRASG12C-mutant tumors. However, patients receiving these agents as monotherapy often develop drug resistance. To address this issue, we evaluated the combination of the PAK4 inhibitor KPT9274 and KRASG12C inhibitors in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). PAK4 is a hub molecule that links several major signaling pathways and is known for its tumorigenic role in mutant Ras–driven cancers. We found that cancer cells resistant to KRASG12C inhibitor were sensitive to KPT9274-induced growth inhibition. Furthermore, KPT9274 synergized with sotorasib and adagrasib to inhibit the growth of KRASG12C-mutant cancer cells and reduce their clonogenic potential. Mechanistically, this combination suppressed cell growth signaling and downregulated cell-cycle markers. In a PDAC cell line–derived xenograft (CDX) model, the combination of a suboptimal dose of KPT9274 with sotorasib significantly reduced the tumor burden (P= 0.002). Similarly, potent antitumor efficacy was observed in an NSCLC CDX model, in which KPT9274, given as maintenance therapy, prevented tumor relapse following the discontinuation of sotorasib treatment (P= 0.0001). Moreover, the combination of KPT9274 and sotorasib enhances survival. In conclusion, this is the first study to demonstrate that KRASG12C inhibitors can synergize with the PAK4 inhibitor KPT9274 and combining KRASG12C inhibitors with KPT9274 can lead to remarkably enhanced antitumor activity and survival benefits, providing a novel combination therapy for patients with cancer who do not respond or develop resistance to KRASG12C inhibitor treatment.

2023-09-01·Biochemistry and biophysics reports

PAK4 inhibition significantly potentiates Gemcitabine activity in PDAC cells via inhibition of Wnt/β-catenin, p-ERK/MAPK and p-AKT/PI3K pathways

Article

作者: Pai, K Sreedhara Ranganath ; Kale, Ramesh ; Samant, Charudatt ; Bokare, Anand ; Verma, Mahip ; Bhonde, Mandar

Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most difficult to treat cancers. Gemcitabine is still the standard of care treatment for PDAC but with modest survival benefit and well reported resistance. Here we explored potential of inhibiting p21 activated kinase 4 (PAK4), a downstream protein of KRAS oncogenic pathway, in combination with Gemcitabine in PDAC cells. PAK4 inhibition by KPT-9274 led to significant potentiation of Gemcitabine activity in PDAC cells, with an increase in apoptosis, DNA damage and cell cycle arrest. At molecular level, PAK4 inhibition dose dependently inhibited Gemcitabine-induced β-catenin, c-JUN and Ribonucleotide Reductase subunit 2 (RRM2) levels. PAK4 inhibition further inhibited levels of phosphorylated ERK (p-ERK); Gemcitabine-induced phosphorylated AKT (p-AKT), phosphorylated and total c-Myc. These results suggest possible role of β-catenin, p-ERK and p-AKT, key effector proteins of Wnt/β-catenin, MAPK and PI3K pathways respectively, in sensitisation of Gemcitabine activity with PAK4 inhibition. Our data unravel probable molecular mechanisms behind combination of PAK4 inhibition with Gemcitabine to counter PDAC, which may be unequivocally proved further with knock down of PAK4. Our findings provide a strong rationale to exploit the combination therapy of Gemcitabine and PAK4 inhibitor for PDAC at pre-clinical and clinical levels.

2023-04-17·Endocrinology

NAD+ Metabolism Generates a Metabolic Vulnerability in Endocrine-Resistant Metastatic Breast Tumors in Females.

Article

作者: Zuo, Qianying ; Yoo, Jin Young ; Erdogan, Zeynep Madak ; Imir, Ozan Berk ; Kaminsky, Alanna Zoe ; Mogol, Ayca Nazli ; Landesman, Yosef ; Walker, Christopher J

Approximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30% to 40% of patients with ER+ breast cancer still experience recurrence and metastasis, with a 5-year relative overall survival rate of 24%. In this study, we identified nicotinamide phosphoribosyltransferase (NAMPT), an important enzyme in nicotinamide adenine dinucleotide (NAD+) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with fulvestrant (Fulv). We tested whether the blockade of NAD+ production via inhibition of NAMPT synergizes with standard-of-care therapies for ER+ MBC in vitro and in vivo. A synergistic effect was not observed when KPT-9274 was combined with palbociclib or tamoxifen or when Fulv was combined with other metabolic inhibitors. We show that NAMPT inhibitor KPT-9274 and Fulv works synergistically to reduce metastatic tumor burden. RNA-sequencing analysis showed that NAMPT inhibitor in combination with Fulv reversed the expression of gene sets associated with more aggressive tumor phenotype, and metabolomics analysis showed that NAMPT inhibition reduced the abundance of metabolites associated with several key tumor metabolic pathways. Targeting metabolic adaptations in endocrine-resistant MBC is a novel strategy, and alternative approaches aimed at improving the therapeutic response of metastatic ER+ tumors are needed. Our findings uncover the role of ERα-NAMPT crosstalk in MBC and the utility of NAMPT inhibition and antiestrogen combination therapy in reducing tumor burden and metastasis, potentially leading to new avenues of MBC treatment.

项与 KPT-9274 相关的新闻（医药）

2023-07-24

·生物谷

北京大学健康科学中心的研究者们指出SLC25A51是一个有吸引力的抗癌靶点

烟酰胺腺嘌呤二核苷酸(NAD+)是一种重要的辅因子，参与多种氧化还原反应，包括糖酵解、柠檬酸循环和氧化磷酸化。烟酰胺腺嘌呤二核苷酸(NAD+)是一种重要的辅因子，参与多种氧化还原反应，包括糖酵解、柠檬酸循环和氧化磷酸化。此外，NAD+也是许多NAD+消耗酶的底物，如聚ADP核糖聚合酶(PAPS)、sirtuins和CD38，这些酶在DNA损伤修复、基因表达调控、细胞周期进展和细胞代谢中发挥重要作用。据报道，癌细胞维持比正常细胞更高的NAD+浓度，以支持能量和大分子的快速产生，以及抵消过量的ROS产生。参与NAD+生物合成的各种酶，包括烟酰胺磷酸核糖基转移酶(NAMPT)和烟酸磷酸核糖基转移酶(NAPRT)，在多种癌症中异常上调，并被认为促进肿瘤的发生和癌症的进展。此外，NAD+降低剂FK866和KPT-9274都是NAMPT的选择性抑制剂，已经进入早期临床试验，显示出很强的降低NAD+水平和诱导癌细胞凋亡的能力，表明NAD+耗竭在癌症治疗中具有巨大的潜力。图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1038/s41418-023-01185-2 近日，来自北京大学健康科学中心的研究者们在Cell Death & Differentiation杂志上发表了题为“SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis”的文章，该研究揭示了SLC25A51是一个有吸引力的抗癌靶点，并提供了一种新型的磷酸氟达拉滨与阿司匹林的药物组合，作为一种潜在的癌症治疗策略。溶质载体家族25成员51(SLC25A51)是最近发现的哺乳动物线粒体NAD+转运蛋白。然而，SLC25A51在癌症等人类疾病中的作用仍未确定。在这里，研究者报告SLC25A51在多种癌症中上调，促进癌细胞增殖。由于SIRT3功能障碍，SLC25A51基因缺失导致线粒体蛋白质乙酰化水平升高，导致作为生物合成关键酶的P5CS酶活性降低，并导致Pro含量降低。值得注意的是，研究者发现FDA批准的药物磷酸氟达拉滨能够与SLC25A51功能结合并抑制其功能，导致线粒体NAD+减少和蛋白质超乙酰化，这可能与阿司匹林进一步协同作用，以增强抗肿瘤效果。阿司匹林与磷酸氟达拉滨协同抑制肿瘤生长图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1038/s41418-023-01185-2 在本研究中，研究者揭示了SLC25A51的促肿瘤作用，通过激活SIRT3和维持线粒体的乙酰化动态平衡来促进癌细胞的增殖。研究者还表明，磷酸氟达拉滨是一种潜在的SLC25A51抑制剂，并可与阿司匹林协同抑制肿瘤生长。总之，本研究为癌症治疗提供了一个新的靶点，并发现了一种可能尽快投入临床使用的有效药物组合。（生物谷 Bioon.com）参考文献 Yutong Li et al. SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis. Cell Death Differ. 2023 Jul 7. doi: 10.1038/s41418-023-01185-2.

寡核苷酸核酸药物临床2期临床终止

2022-07-05

·生物制品圈

拜耳布局NAMPT抑制剂新型ADC平台，Seagen也曾“撒网”

前言——NAMPT是个啥？NAMPT(Nicotinamide Phosphoribosyl Transferase，烟酰胺磷酸核糖转移酶)是NAD(Nicotinamide Adenine Dinucleotide，简称辅酶I)补救合成过程中的一个限速酶，它能催化烟酰胺（NAM）合成β-烟酰胺单核苷酸(NMN), NMN进而在NMNAT作用下转化为NAD。所以，NAM作为NAD的前体之一，在NAM转化为NAD的过程中，如果对NAMPT酶进行抑制，导致NAM无法合成NMN，最终导致NAD的合成受限。NAD是一种转递质子的辅酶，参与细胞物质代谢、能量合成、DNA修复等多项重要生理活动，维持足够的细胞内NAD含量对于所有细胞的存活至关重要，肿瘤患者体内细胞内与细胞外NAMPT均比正常对照有明显升高。 2018年Seagen探索了NAMPT抑制剂作为payload的可能性，相关结果发表在2018年的AACR会议上。近期，拜耳科学家在Bioconjugate Chemistry期刊上也发表了利用NAMPT抑制剂作为payload的研究文章。本篇我们主要以拜耳的这篇paper为主线对NAMPT抑制剂的payload平台做以解析，另外用Seagen的数据作为补充。01 先初步设计3种不同的liner-payload看看效果首先设计了EC1-EC3 3个linker-payload,母核结构如下：具体的结构如下图，linker接头均采用马来酰亚胺的接头，linker和payload之间我自己用红色的线给隔开，其中EC1和EC2为不可裂解linker；EC3采用的为mc-VA的酶切型linker，payload和EC1一样。接下来同时在C4.4a、HER2、B7H3 3个靶点上进行了开发。细胞活性上：payload相同的情况下，可裂解的linker EC3细胞活性明显好于不可裂解的linker EC1。关于细胞活性，小编补充：ADC细胞杀伤活性的检测，文献大多采用CTG试剂盒进行检测，其原理是基于细胞内ATP的水平；其实检测细胞活性的方法非常多，基于的原理也千差万别，拜耳的检测也是用的CTG的试剂盒，但Seagen在2018年的文献中提过，该方法做出的ADC的in vitro体外活性数值和in vivo动物药效并不完全一致，反而是以NAD水平的检测方法与in vivo动物药效对应关系更好。拜耳的科学家在此步检测时用的基于ATP水平的CTG检测法，但在单独筛选payload和后续优化ADC后也均采用两种指标同时作为检测手段，这提示研发人员一定要深刻的理解自己所研究药物发挥作用的机制，从而开发适合自己的活性assay，准确可靠的体外活性assay往往能事半功倍。02 基于药代进一步优化liner-payload 对EC3偶联的ADC进行了药代分析，发现除了本身的毒素Compound4外，还存在完整的linker-payload p-14,以及衍生出来的其他磷酸化产物。于是，接着优化第一步：更改linker,避免毒素部分过早的从抗体上发生解离。因为环状的MC接头在体内容易被带有巯基的抗体或者蛋白取代（发生交换反应），改成带负电的线性succinic amide接头后则不再与其他巯基交换，理论上药代上性质会更稳定，于是产生了EC4；第二步：降低代谢物旁观效应，扩大安全窗口。在EC4的基础上，payload上增加了一个喹啉基团，同时辅以PEG链增加水溶性帮助获得更高DAR值，产生了EC5。细胞活性上看，不管是单独的payload还是偶联成ADC后，EC5并没有取得意想中的效果，于是后续用EC4偶联的ADC进行体内药效评价。值得一提的是，EC4偶联的B7-H3-EC4，细胞活性的IC50可达低至7pM的水平，而HER2-EC4的IC50更是在0.3pM以下。03 in vivo动物药效 B7H3 ADC（DAR=7.8）治疗组，5 mg/kg剂量下, 7day一次，给药3次，7只小鼠中6只肿瘤完全消失，1只肿瘤缩小。此外，动物的体重也稳步上升，提示较好的安全性。HER2 ADC（10 mg/kg剂量下, 7day一次，共给药7次），治疗后7只小鼠肿瘤全部缩小（T/C=0.13），且停止治疗后肿瘤没有重新生长。C4.4a治疗组（10 mg/kg剂量下, 7day一次，共给药7次），8只小鼠中3只小鼠肿瘤缩小，5只小鼠疾病稳定（SD）。另外，该两组动物体重均有不同程度的下降，这个跟给药剂量和给药次数过多可能有关系，但同时也表明存在潜在的有效性风险。小编补充：MDA-MB-453细胞系是同时表达HER2和C4.4a的，HER2的表达量为C4.4a的4倍（80,000 antigen/cell VS 20,000 antigen/cell ）,此处也能看出，抗原表达量更高时，药效确实会更好。04 NAMPT抑制剂开发状况目前针对NAMPT抑制剂已有两款小分子处在临床阶段，padnarsertib（KPT-9274，由Karyopharm Therapeutics Inc开发，国内徳琪医药合作开发，目前处于临床II期）；OT-82（由OncoTartis Inc开发，目前处于临床I期）。而在此之前也曾有过针对NAMPT抑制剂开发的尝试，比如由Apoxis 开发的daporinad（APO-866）在细胞活性上IC50上可达1nM，但后来在连续三项分别针对B细胞慢性淋巴细胞白血病 (B-CLL) 、皮肤T细胞淋巴瘤(CTCL)、黑色素瘤的临床中均折戟沉沙。nM这个水平的细胞活性，单独用作化药治疗会因为毒性太强导致安全窗口过窄而做不出有效性，但作为ADC payload来用的话或许是大有空间的。另外，关于NAMPT抑制剂，此处我能想到的一个潜在风险是，抑制了NAD的补救合成途径后，其他旁路途径是否还可以作为补充，以及补充的效果如何仍待仔细研究一下，具体临床效果怎么样，还需期待拜耳的后续。参考文献[1] Sampath, Deepak, Misner, et al. Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer, 2015.[2] Valentina, Audrito, Antonella, et al. Targeting metabolic reprogramming in metastatic melanoma: the key role of nicotinamide phosphoribosyltransferase (NAMPT), 2019.[3] Niels Böhnke, Markus Berger, Nils Griebenow, et al. A Novel NAMPT Inhibitor-Based Antibody− Drug Conjugate Payload Class for Cancer Therapy, 2022. （拜耳paper）[4] Neumann C S , Olivas K C ,Anderson M E , et al. Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody-Drug Conjugates, 2018. （Seagen paper）识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

小分子药物免疫疗法AACR会议合作抗体药物偶联物抗体

100 项与 KPT-9274 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床2期	-	德琪医药有限公司	2022-06-22
霍奇金淋巴瘤	临床1期	中国	Emerson Resources, Inc.	2022-06-30
霍奇金淋巴瘤	临床1期	中国	Karyopharm Therapeutics, Inc.	2022-06-30
霍奇金淋巴瘤	临床1期	中国	上海德琪医药科技有限公司	2022-06-30
难治性急性髓细胞白血病	临床1期	美国	Karyopharm Therapeutics, Inc.	2021-08-27
复发性急性髓细胞白血病	临床1期	美国	Karyopharm Therapeutics, Inc.	2021-08-27
晚期恶性实体瘤	临床1期	美国	Karyopharm Therapeutics, Inc.	2016-06-01
晚期恶性实体瘤	临床1期	加拿大	Karyopharm Therapeutics, Inc.	2016-06-01
非霍奇金淋巴瘤	临床1期	美国	Karyopharm Therapeutics, Inc.	2016-06-01
非霍奇金淋巴瘤	临床1期	加拿大	Karyopharm Therapeutics, Inc.	2016-06-01

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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


NCT02702492 (ESMO2017) 人工标引	临床1期	晚期恶性实体瘤 \| 非霍奇金淋巴瘤	14	Niacin+KPT-9274	積獵製製遞壓壓憲鑰鬱(簾鹽構網夢簾壓願觸獵) = Not reached 夢糧廠積願願襯鹽衊構 (餘觸夢膚鹹淵夢醖餘廠 ) 更多	积极	2017-09-09
NCT02702492 (AACR2017)	临床1期	晚期恶性实体瘤 \| 非霍奇金淋巴瘤	60	KPT-9274	齋願壓餘構膚願淵範鹹(鬱鹹遞齋襯廠壓醖壓鑰) = Doses up to 4 mg/kg KPT-9274 were well tolerated with no grade ≥3 toxicities. At 4.5 mg/kg one dog exhibited severe vomiting, diarrhea, collapse, anemia and thrombocytopenia, establishing 4 mg/kg as MTD. No unexpected toxicities were noted with the combination when compared to those expected from DOX alone. 鬱淵夢製艱衊餘糧鹽簾 (顧艱衊繭齋繭衊壓選廠 ) 更多	积极	2017-07-01