Phase 1/1b, First-in-Human, Dose-Escalation and Expansion Study of FLX925 Administered Orally to Subjects With Relapsed or Refractory Acute Myeloid Leukemia

This first-in-human (FIH) clinical trial is a Phase 1/1b, open-label, sequential-group, dose-escalation and cohort expansion study evaluating the safety, PK, PD, and antitumor activity of FLX925 in subjects with relapsed or refractory AML.

开始日期2015-04-08

申办/合作机构

Rapt Therapeutics, Inc.

100 项与 FLX-925 相关的临床结果

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100 项与 FLX-925 相关的转化医学

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100 项与 FLX-925 相关的专利（医药）

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项与 FLX-925 相关的文献（医药）

2025-01-23·JOURNAL OF MEDICINAL CHEMISTRY

Elucidating Binding Selectivity in Cyclin-Dependent Kinases 4, 6, and 9: Development of Highly Potent and Selective CDK4/9 Inhibitors

Article

作者: Xing, Yajie ; Cao, Qixiong ; Chen, Jiean ; Wang, Rui ; Pan, Shuqiong ; Yang, Qianqian ; Feng, Meixi ; He, Zhipeng ; Huang, Yong ; Jiang, Chenran ; Lian, Chenshan ; Kang, Wei ; Yang, Jinglei ; Liu, Zhihong ; Wu, Yun-Dong ; Yin, Feng ; Ye, Yuxin ; Zhao, Juan ; Song, Chunli

CDK4/6 inhibitors are effective in treating HR⁺/HER2^- breast cancer but face limitations due to therapeutic resistance and hematological toxicity, particularly from strong CDK6 inhibition. To address these challenges, designing selective inhibitors targeting specific cyclin-dependent kinases (CDK) members could offer clinical advantages and broaden CDK inhibitor indications. However, the highly conserved binding pockets of CDKs complicate selective targeting. This study leverages in silico modeling and structural analysis of cocrystal data to identify subtle differences in key CDK binding pockets. Notably, a sequence difference in the αD-helix motif between CDK4 and CDK6 provides a targetable "sweet spot" for selectivity. By incorporating a 1,4-trans-cyclohexanediamine side chain, we designed molecules that favor interactions with CDK4 over CDK6 and explored potential dual CDK4/9 inhibition. This approach yielded a lead compound with distinct in vitro selectivity and promising in vivo pharmacokinetics, offering valuable insights for the development of selective next-generation CDK inhibitors.

2021-06-01·Annals of hematology3区 · 医学

High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells

3区 · 医学

Article

作者: Andreeff, Michael ; Daver, Naval ; Zeng, Zhihong ; Kantarjian, Hagop M ; Konopleva, Marina ; Ly, Charlie ; Cortes, Jorge

FLT3 mutations, which are found in a third of patients with acute myeloid leukemia (AML), are associated with poor prognosis. Responses to currently available FLT3 inhibitors in AML patients are typically transient and followed by disease recurrence. Thus, FLT3 inhibitors with new inhibitory mechanisms are needed to improve therapeutic outcomes. AMG925 is a novel, potent, small-molecule dual inhibitor of FLT3 and CDK4/6. In this study. we determined the antileukemic effects and mechanisms of action of AMG925 in AML cell lines and primary samples, in particular AML stem/progenitor cells. AMG925 inhibited cell growth and promoted apoptosis in AML cells with or without FLT3 mutations. Reverse-phase protein array profiling confirmed its on-target effects on FLT3-CDK4/6-regulated pathways and identified unrevealed signaling network alterations in AML blasts and stem/progenitor cells in response to AMG925. Mass cytometry identified pathways that may confer resistance to AMG925 in phenotypically defined AML stem/progenitor cells and demonstrated that combined blockade of FLT3-CDK4/6 and AKT/mTOR signaling facilitated stem cell death. Our findings provide a rationale for the mechanism-based inhibition of FLT3-CDK4/6 and for combinatorial approaches to improve the efficacy of FLT3 inhibition in both FLT3 wild-type and FLT3-mutated AML.

2018-12-01·Journal of hematology & oncology1区 · 医学

FLT3 inhibitors in acute myeloid leukemia

1区 · 医学

ReviewOA

作者: Zhu, Xiongpeng ; Wu, Mei ; Li, Chuntuan

FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents.

项与 FLX-925 相关的新闻（医药）

2024-01-15

·CPHI制药在线

研发 | PIM激酶抑制剂，开启新一轮激酶抑制剂的研发热潮

关注并星标CPHI制药在线导读激酶抑制剂是药物研发史上的一个里程碑，以格列卫为代表的激酶抑制剂更是因为电影《我不是药神》而闻名大众。在抗癌药物的研发史上，激酶抑制剂是一个不能或缺的名字。 PIM激酶是经过充分研究的癌症药物靶点，属于丝氨酸/苏氨酸激酶家族。它们是各种信号通路的下游靶点，它们的上调/下调影响各种生理过程。PIM 家族包括三种亚型，即 PIM-1、PIM-2 和 PIM-3，它们在不同类型的癌症中具有不同的表达水平。它的结构在铰链区域显示出一个独特的ATP结合位点，这使得它在其他激酶中独一无二。 PIM激酶广泛报道用于血液系统恶性肿瘤以及前列腺癌和乳腺癌。目前，许多药物被用作PIM激酶的抑制剂。图1 近年针对激酶的药物Moloney 鼠（PIM）激酶的前病毒整合最初被认为是 Moloney 鼠白血病病毒（MMLV）的前病毒整合位点，该病毒可产生 T 细胞淋巴瘤。PIM是一种编码丝氨酸/苏氨酸激酶的原癌基因，属于钙/钙调蛋白调节激酶（CAMK）家族。它以三种亚型（PIM-1、PIM-2、PIM-3）存在，显示出高度的序列相似性。它们具有组成型活性，因为在其结构中没有发现调控结构域，表明它们不依赖于转录后修饰。它们在造血、上皮细胞谱系、血管平滑肌和胚胎干细胞中表达，并在转录和翻译水平上受各种生长因子、细胞因子和白细胞介素的调控。它们是细胞增殖、细胞周期调节、细胞存活、细胞凋亡和迁移的关键组成部分。此外，其缺乏导致细胞生长和存活率下降。当过表达时，它们会引起造血和实体瘤，通过细胞周期进程和细胞凋亡诱导恶性肿瘤。 PIM激酶的异常表达在不同的癌症中遵循亚型特异性模式。例如，PIM-1主要在多种血液系统恶性肿瘤和实体瘤中表达。同时，PIM-2 在骨髓瘤、淋巴瘤和白血病中表达明显。相比之下，PIM-3 过表达主要见于腺癌。此外，它们还参与癌症中细胞存活和细胞周期进程基因的转录激活。令人兴奋的是，它们在神经退行性疾病中的作用也被观察到。此外，PIM-1在免疫治疗、衰老、表观遗传学等方面也发现了各种功能。例如，PIM激酶在心脏治疗中诱导了再生、存活、增殖和衰老。PIM-1对人类心脏祖细胞具有心脏保护作用，可响应DNA损伤、端粒缩短或环境因素。同样，PIM激酶也显示淋巴细胞和NK细胞通过细胞因子的产生和NF-kB、MYC和mTOR通路的激活介导免疫调节反应。值得注意的是，各种促肿瘤信号分子，如MYC、CDC25、Notch1 和 BAD 被报道为 PIM 激酶的下游靶标，促进癌症的进展。图2 MIK激酶的作用机制在几种恶性肿瘤中，PIM 家族的过表达与总生存期、治疗耐药性和癌细胞增殖的降低有关。PIM与其他致瘤通路（如PI3K/mTOR/AKT通路，以及抑癌基因和癌基因）的相互作用可以驱动细胞生长和存活、增殖和逃避细胞凋亡。此外，PIM的过表达导致对传统化疗、放疗、PI3K抑制剂、MET抑制剂、抗HER2/EGFR治疗、免疫抑制剂雷帕霉素和其他治疗策略的耐药性。PIM 活性主要受 JAK/STAT、NFκB 和 HSP90 通路在转录和蛋白稳定水平上的调控。PIM信号的这种不同的相互作用及其在对其他治疗方式的耐药性中的作用为PIM与其他治疗的联合靶向以提高疗效提供了强有力的理由。此外，PIM激酶是预防癌症的潜在靶标，因为它们具有独特的结构，包含铰链区，与其他激酶不同，铰链区形成独特的ATP结合位点。值得注意的是，PIM激酶家族的大多数结构信息仅限于PIM-1；因此，它一直专注于当前的研究，以了解抑制剂开发的药理学。已经设计了几种抑制剂来靶向表现出耐药性的PIM-1相关疾病。它们属于不同的杂环支架，包括吡/咯、嘧啶、噻唑烷、苯并呋喃、吲哚、三唑、噁二唑和喹诺酮类。大多数ATP竞争性抑制剂（包括SGI-1776、AZD1208和LGH447）已进入治疗急性髓系白血病、前列腺癌淋巴瘤或多发性骨髓瘤的临床试验。因此，非ATP模拟抑制剂是针对ATP结合口袋的非铰链侧的抑制剂设计的新希望，可在激酶之间提供结构多样性。近年，晟科药业宣布PIM3和CDK4/6 双靶点抑制剂ETH-155008在澳洲完成首例非霍奇金淋巴瘤（NHL）受试者6个疗程给药，未见任何药物相关的不良反应。ETH-155008临床I期（NCT04840784）是一项开放、多中心、剂量递增及剂量拓展的临床研究，旨在评价其单药在血液肿瘤（非霍奇金淋巴瘤及急性髓细胞白血病）患者的安全性、耐药性、药代动力学及初步疗效。ETH-155008由晟科药业自主研发，拥有100%自主知识产权。是全球第一款（真正意义上的 First in Class）进入临床研究阶段的靶向PIM3和CDK4/6 双靶点抑制剂。目前已有三种FTL3抑制剂midostaurin、gilteritinib和quizartinib获批用于AML的临床治疗。ETH-155008 对关键靶酶具有很强的抑制活性（FLT3 IC50 为 0.5nM；Flt3-Itd IC50 为 0.6nM；CDK4/D1 IC50 为 0.8nM，CDK6/D1 IC50为1.4nM）。比测试的阳性对照 gilteritinib、quizartinib 和 AMG-925 更有效。ETH-155008 对培养的人急性髓细胞白血病细胞（MV4-11 和 Molm-13）具有高效的抗增殖活性，IC50 分别为 4.1nM 和 12nM，并在体内显示出显着的抗肿瘤功效。ETH-155008 的抗肿瘤活性与 gilteritinib相当，但比 midostaurin 好得多，后者在两种 FLT3 突变模型中仅显示出温和的抗肿瘤活性，TGI 约为 25%。ETH-155008 治愈了所有荷瘤小鼠（治疗时的平均肿瘤大小为 126 mm3），剂量为 40mg/kg /每天一次，持续 14 天，这表明毒性非常小（仅 2% 体重减轻），远低于最大耐受剂量。ETH-155008 代表了一种新型的双重抑制剂，它可能通过 FLT3 和 CDK4/6 的双重靶向来实现有效 AML 治疗。至今还没有被批上市的PIM抑制剂，美国Incyte 制药研发的泛PIM靶点抑制剂 INCB053914 （治疗NHL和多发性骨髓瘤）和Menarini 制药公司研发的PIM/FLT3 双靶点抑制剂SEL24（AML和骨髓纤维化）目前都处于临床II期试验中。图3 PIM3和CDK4/6 在生命体中的作用参考资料： 1. Rathi A, Kumar D, Hasan G M, et al. Therapeutic targeting of PIM KINASE signaling in cancer therapy: structural and clinical prospects[J]. Biochimica et Biophysica Acta (BBA)-General Subjects, 2021, 1865(11): 129995. 2. Chen L, Mao W, Ren C, et al. Comprehensive Insights that Targeting PIM for Cancer Therapy: Prospects and Obstacles[J]. Journal of Medicinal Chemistry, 2024. 3. Liu C, Liu B, Xu C, et al. ETH-155008, a novel selective dual inhibitor of FLT3 and CDK4/6 in preclinical treatment of acute myeloid leukemia[J]. 2019. 作者简介：roger，广东广州人，硕士研究生，工程师，主要研究方向为分析方法学，仪器原理与研制，凝聚态物理，电学理论与超导体理论，理论物理等等。智药研习社1月直播预告来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

2016-09-16

·BioSpace

Could Biotech’s Bestie Celgene Be Getting Ready to Unveil Another Deal?

September 16, 2016 By Alex Keown , BioSpace.com Breaking News Staff SUMMIT, N.J. – Is Celgene about to close a deal to acquire another company? It appears the company is looking to snap up Swiss-based EngMab AG , the maker of T-cell bispecific antibodies and B-cell maturation antigens. A filing with the U.S. Federal Trade Commission shows a Sept. 13 acquisition of EngMab, but as of now, Celgene said there’s no deal, Endpoints reported. EngMab has licensed its T-cell technology from Roche , Endpoints said. “ A deal has not completed ,” a Celgene spokesperson told Endpoints in an email. “We cannot comment any further at this time.” Endpoints noted that Celgene, which has become a best-friend of sorts to multiple companies across the industry, is heavily involved with the type of work that EngMab is doing, which would make that company a good fit under the Celgene umbrella. Since 2014 Celgene has spent more than $3 billion in partnerships, most noticeably the $1 billion the company invested in a 10-year partnership with Juno Therapeutics or the more recent deal with Jounce Therapeutics that could be worth up to $2.5 billion. Celgene also has collaborations with companies like Agios , Bluebird Bio , Epizyme and others. In 2014, Celgene entered into 10 deals, shelling out an average of $222 million in upfront payments to its partners. Celgene’s partnership goals has been a strategic effort to diversify revenue streams so it is not so financially dependent on its blockbuster blood cancer drug, Revlimid . Another startup that Celgene backed recently is California-based FLX Bio , a company specializing in cancer treatments. FLX’s FLX925 is a selective inhibitor of FLT3 and CDK4/6 and is being studied in a proof-of-concept study in patients with acute myeloid leukemia. The drug is moving into a Phase I clinical trial. FLX925 ‘s dual-inhibitor action may be more effective in treating FLT3-mutated AML than other FLT3 inhibitors, resulting in greater clinical benefit. Furthermore, FLX925 has the potential to treat a wider array of cancers beyond AML, the company said on its website—again, an area of interest to Celgene. In April Celgene Corporation struck two deals with other pharmaceutical companies with a combined value of $110 million to advance its oncology platform, continuing the cancer drugmaking company’s deal making trend to advance its oncology pipeline. Celgene entered into an $80 million agreement with Agios Pharmaceuticals, Inc. to develop AG-881, a small molecule that has shown in preclinical studies to fully penetrate the blood brain barrier and inhibit isocitrate dehydrogenase-1 (IDH1) and IDH2 mutant cancer models. Celgene also announced today it struck a $30 million agreement with one-year-old Canada-based Northern Biologics to advance that company’s work in oncology and fibrosis therapeutics. Citing Jeffries analyst Brian Abrahams , Endpoints said EngMab’s experimental drug EM801 “was potent and showed dose-dependent killing of the primary MM cells.” “We continue to see BCMA as a promising target in MM, given the target is estimated to be present in 60 to 70 percent of myeloma cases, is primarily expressed by plasma cells, and does not appear to be heavily involved in other B cells processes,” Abrahams said, according to Endpoints.

临床1期并购

2016-04-27

·BioSpace

Backed by Celgene, Bay Area Startup FLX Bio Bags $50 Million to Push Lead Drug into Clinic

April 27, 2016 By Alex Keown , BioSpace.com Breaking News Staff SOUTH SAN FRANCISCO – Backed by a Celgene investment, California-based startup FLX Bio nabbed $50 million in Series B financing to push its early stage cancer drug through early trials, the company announced this morning. FLX’s FLX925 is a selective inhibitor of FLT3 and CDK4/6 and is being studied in a proof-of-concept study in patients with acute myeloid leukemia. The drug is moving into a Phase I clinical trial. FLX925’s dual-inhibitor action may be more effective in treating FLT3-mutated AML than other FLT3 inhibitors, resulting in greater clinical benefit. Furthermore, FLX925 has the potential to treat a wider array of cancers beyond AML, the company said on its website. In addition to FLX925, FLX also has two pre-clinical immuno-oncology programs in early development. Brian Wong , president and chief executive officer of FLX, said the funds will help the company expand the treatment options for cancer patients by developing novel compounds focused on inhibiting the activity of regulatory T cells and myeloid cells. Myeloid cells are responsible for suppressing the immune system’s ability to kill cancer cells. Before helming FLX, Wong was head of the immuno-oncology program at Five Prime Therapeutics Inc. , the San Francisco Business Times reported. The $50 million raised in the latest round will go nicely with $29 million in Series A funding privately-held FLX previously raised. That makes $79 million in less than one year since FLX Bio was founded. The Series B financing was supported by multiple venture capital and biotech groups, including The Column Group (TCG) , Topspin Partners , Kleiner Perkins Caufield & Byers (KPCB) and Celgene . This is certainly not the first time Celgene has bought a stake in a company working on immuno-oncology therapies. Last year, Celgene acquired a $1 billion stake in Seattle-based Juno Therapeutics as the two companies entered into a 10 year collaborative agreement to leverage combined immunology and oncology expertise to develop treatments for cancer and autoimmune diseases. Bob Hugin , CEO of Celgene, said the Juno deal is the third significant partnership over the past six months and expects to see revenue from the collaborations by 2020. In April Celgene Corporation struck two deals with other pharmaceutical companies with a combined value of $110 million to advance its oncology platform, continuing the cancer drugmaking company’s deal making trend to advance its oncology pipeline. Celgene entered into an $80 million agreement with Agios Pharmaceuticals, Inc. to develop AG-881, a small molecule that has shown in preclinical studies to fully penetrate the blood brain barrier and inhibit isocitrate dehydrogenase-1 (IDH1) and IDH2 mutant cancer models. Celgene also announced today it struck a $30 million agreement with one-year-old Canada-based Northern Biologics to advance that company’s work in oncology and fibrosis therapeutics.

临床1期免疫疗法引进/卖出蛋白降解靶向嵌合体

100 项与 FLX-925 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
难治性急性髓细胞白血病	临床1期	美国	Rapt Therapeutics, Inc.	2015-04-08
复发性急性髓细胞白血病	临床1期	美国	Rapt Therapeutics, Inc.	2015-04-08
急性髓性白血病	临床1期	-	Amgen, Inc.	-
肿瘤	临床前	美国	Amgen, Inc.	2014-04-02

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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


AACR2015	临床1期	-	-	FLX925 (AMG 925)	繭醖網窪積夢網膚夢鹹(範蓋願窪顧鬱積壓遞繭) = 鹹範遞醖蓋構積築顧壓膚糧淵壓糧遞淵糧獵積 (鑰醖醖製鹽範獵繭獵鬱 )	-	2015-08-01