Glasdegib Maleate

注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。G 蛋白偶联受体（G protein-coupled receptor，简称：GPCR）是一大类膜蛋白受体的统称，它们组成了一个庞大的、超过800个人类基因编码的蛋白质超家族。GPCR具有保守结构，包含7 个跨膜跨膜螺旋，激活受体的胞内区域可招募并结合下游效应蛋白，通过其信号通路的协同作用调节多种生理过程。图1:G蛋白偶联受体G α亚基的激活。从图中可以看出明显的7个跨膜结构，以及GPCR被配体激活后G α激活并可激活细胞内下游信号的过程© 2002 Nature Publishing Group Li, J. et al. The Molecule Pages database. Nature 420, 716-717 (2002). All rights reserved. View Terms of Use由于GPCR在人体内表达的的广泛性和重要性，GPCR也经常被视作“当代生物医药最大的药物靶标蛋白家族”，根据统计，已上市的药物中有超过40%的药物都以GPCR家族成员为靶点。已有的研究显示，GPCR与癌症、炎症、代谢性疾病这三大类困扰人类的疾病都存在着密切的关系。此外，GPCR在心血管疾病、病原体感染乃至阿尔兹海默病等的研究中也有参与。GPCR与癌症GPCR家族的多个成员都被证实与各种癌症的发生和进展相关。典型的如SMO蛋白，它是Hh（Hedgehog）信号通路中的关键蛋白。Hh信号通路与胚胎发育相关，它的异常活化可以导致基底细胞癌、成神经管细胞瘤和横纹肌肉瘤等多种癌症。已获批上市的3款SMO抑制剂中，罗氏旗下的Vismodegib和诺华旗下的Erismodegib都用于治疗基底细胞癌，而辉瑞的Glasdegib被批准用于急性髓系白血病。又例如趋化因子CXCR4，近年来研究发现，肿瘤细胞转移到特定器官是不同器官通过趋化作用吸引特定类型肿瘤细胞归巢的结果。而在众多的趋化因子受体中，CXCR在许多肿瘤中都存在表达增强。目前的研究表明，与趋化因子受体CXCR4相关的癌症超过23种，它被认为在血管生成和介导肿瘤细胞定向迁移、侵袭和转移中发挥着重要的作用。此外，还与HIV病毒的侵袭相关。它的首款药物CXCR4拮抗剂Plerixafor，于2008年被FDA批准用于血液恶性肿瘤。GPCR与代谢性疾病随着现代人类生活方式的改变，代谢性疾病，特别是糖尿病、脂肪肝和肥胖症等已经对人类健康构成了很大威胁。而葡萄糖依赖的促胰岛素受体GPR119被认为是一种治疗糖尿病、脂肪肝和肥胖症等代谢性疾病的潜在药物靶点。GPR119是G蛋白偶联受体（GPCR）超家族中的一种孤儿受体。主要分布在胰岛b细胞和胃肠道L细胞，调节葡萄糖依赖的促胰岛素的分泌。GPR119的激活可以刺激胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素释放多肽（GIP）的分泌，这两种激素是调控体内糖代谢平衡的重要物质。近年来，越来越多的GPR119小分子激动剂被开发，作为开发口服治疗糖尿病的临床药物。然而，由于对GPR119功能和激活机制理解的匮乏，限制了靶向GPR119的小分子药物的开发。因此对于此靶点更深入的分子水平研究成为该领域重要的研究热点，而揭示GPR119与内源性配体以及药物分子的相互作用机制也成重要的科学问题。此外，GPR119被一直认为有较高“自激活”活性，但这种“自激活”的原因和结构基础尚不明确。2022年8月15日，中科院上海药物研究所徐华强研究员、谢欣研究员，联合临港实验室蒋轶研究员，在Nature Structural & Molecular Biology发表了最新的研究成果“Structural identification of lysophosphatidylcholines as activating ligands for orphan receptor GPR119”。本研究首次报道孤儿受体GPR119偏好性结合LPC的分子机制，提出部分所谓具有“自激活”活性的受体可能是由于结合了未知配体而导致的观点；首次解析了GPR119与内源性配体LPC以及临床候选小分子药物APD668的结构，揭示了GPR119被小分子激活的结构基础；同时发现了GPR119独特的结构特征和潜在的别构调节剂的结合位点，为靶向GPR119的代谢性疾病药物开发提供了重要结构基础。GPCR与甲状腺相关疾病在中国，甲状腺相关疾病的总患病率达到20%。包括甲状腺功能亢进（甲亢）、甲状腺功能减退（甲减）、甲状腺结节，以及甲状腺癌在内的疾病给国人的健康生活造成了很大威胁。健康状态下，甲状腺的主要生理功能是分泌甲状腺素调控机体能量代谢，而这一功能的实现依赖于甲状腺细胞表面的促甲状腺素受体（TSHR，是G蛋白偶联受体超家族的一员）感知垂体细胞分泌的促甲状腺素（TSH）信号。临床发现，TSH可作为重要的药物分子用于辅助治疗甲状腺癌、McCune-Albright综合征、垂体促甲状腺激素腺瘤以及原发性先天性甲状腺功能减退症在内的多种罕见病，但是，TSH如何作用于TSHR的分子机制尚不明了，而自身免疫性甲亢、甲减仍无有效的治疗手段。2022年8月8日，中国科学院上海药物研究所徐华强研究员联合临港实验室蒋轶研究员、北京协和医院张抒扬教授，共同在Nature杂志上发表了最新研究成果“Hormone- and antibody-mediated activation of the thyrotropin receptor”。该项工作首次揭示了TSH与TSHR相互作用的细节模式，阐明了决定TSH和TSHR特异性识别的关键氨基酸残基，并揭示了TSH激活TSHR的分子机制，揭示了抗体激活或抑制受体从而引发GD和Hashimoto’s disease的分子机制，并进一步揭示了小分子别构激动剂ML-109与受体TSHR相互作用细节模式，为临床开发用于治疗甲状腺相关疾病的抗体或小分子药物提供了结构依据。小结虽然GPCR作为药物开发靶点的重要性被广泛认可，但SBDD（基于结构的药物设计，structure-based drug design）仍要受限于靶标结构的公布。如何改善解析GPCR结构的效率，使之更匹配药物开发的周期，也将成为研究人员接下来的挑战。为了探究更多GPCR相关内容，赛默飞联合药融圈，以《显微成像新宇宙，药物研发基础研究新革命》为主题，邀请中国科学院上海药物研究所研究员徐华强老师、中国科学院上海药物研究所助理研究员段佳老师以及中国科学院上海药物研究所、上海市高峰电镜中心工程师袁青宁老师，就当下结构生物学应用与发展前景展开讨论，跟随药物研发革命的浪潮，提供药物研发清晰地模板和思路。2022年11月17日下午13:00，与您不见不散！

Dublin, April 12, 2021 (GLOBE NEWSWIRE) -- The "Disease Analysis: Acute Myeloid Leukemia (AML)" report has been added to ResearchAndMarkets.com's offering. AML is a type of heterogeneous hematological malignancy that originates from immature white blood cells (blasts) in the bone marrow, which may be derived from either a hematopoietic stem cell or a lineage-specific progenitor cell. "Acute" means that the leukemia may progress rapidly - AML generally spreads quickly to the bloodstream and can then spread to other parts of the body including the lymph nodes, spleen, central nervous system, and testicles.Latest Key TakeawaysThe publisher estimates that in 2018, there were 158,400 incident cases of acute myeloid leukemia (AML) worldwide and expects that number to increase to 169,000 incident cases by 2027. Approximately 60% of newly diagnosed patients are eligible for intensive chemotherapy, such as the 7+3 regimen of cytarabine and daunorubicin.Since 2017, there have been nine new drugs approved for AML in the US, dramatically changing the treatment landscape. Gone is the era where all front-line patients received either 7+3 chemotherapy or a hypomethylating agent (decitabine or azacitidine). Many of the new therapies target specific segments of AML or patients with specific mutations. As such, there is currently little competition between the new therapies, but that will change as therapies receive label expansions and new competitor therapies are approved.Two FLT3 inhibitors have been approved for FLT3-mutated AML: Rydapt for front-line patients eligible for intensive chemotherapy, and Xospata for relapsed/refractory patients. Rydapt may soon face competition in the front-line FLT3 setting as quizartinib, crenolanib, and Xospata are being evaluated in combination with standard chemotherapy and as single-agent maintenance therapies following either chemotherapy consolidation or hematopoietic stem cell transplant (HSCT). Approval in the lucrative maintenance setting would give these drugs a favorable long-term commercial outlook. Approximately 25-30% of AML patients have an FLT3 mutation.Tibsovo and Idhifa are approved in the US as oral, single-agent therapies for relapsed/refractory AML patients with IDH1 and IDH2 mutations, respectively. Tibsovo is also approved as a monotherapy for front-line patients over the age of 75 years. Both of these IDH inhibitors are now in Phase III trials in combination with standard induction (7+3) and consolidation chemotherapy and as maintenance therapy in front-line AML. Tibsovo is also being investigated in combination with azacitidine in a Phase III trial in front-line patients. Approval of Tibsovo and Idhifa in the EU will depend on these Phase III results. Tibsovo may face competition from FT-2102, an IDH1 inhibitor being evaluated in the relapsed/refractory setting in a pivotal single-arm Phase II trial. IDH1 mutations are present in 6-9% of AML, while IDH2 mutations are present in approximately 12% of cases.Mylotarg, an antibody-drug conjugate targeting CD33, is the only monoclonal antibody therapy approved for AML. Mylotarg combined with intensive chemotherapy is recommended for newly diagnosed patients with favorable cytogenetic risk (approximately 10% of patients eligible for intensive chemotherapy). Over 90% of AML patients are positive for CD33 expression.Vyxeos, a liposomal formulation of the 7+3 chemotherapy regimen, was approved in the US and EU for the treatment of newly diagnosed patients with secondary AML after showing an improvement in overall survival compared to the 7+3 regimen in patients ?60 years of age. Secondary AML accounts for approximately one third of new AML diagnoses, but most of these patients will be too frail for Vyxeos. Approximately 16% of patients eligible for intensive chemotherapy have secondary AML. Market access for Vyxeos is strengthened by positive recommendations from the US Centers for Medicare and Medicaid Services and from NICE in England and Wales.Venclexta combined with azacitidine is the new standard of care for newly diagnosed AML patients not suited for intensive chemotherapy (approximately 40% of newly diagnosed patients). A confirmatory Phase III trial evaluating Venclexta + azacitidine demonstrated a survival advantage (15 months versus 10 months) and supported regulatory submissions to European and Japanese authorities, with approvals expected in 2021. Venclexta is currently being evaluated in combination with novel agents in several trials, and a Phase III study (VIALE-M) is evaluating Venclexta combined with azacitidine as maintenance therapy for AML patients in first remission after conventional chemotherapy.Daurismo is the first and only Hedgehog pathway inhibitor approved for AML. Daurismo is approved in combination with low-dose cytarabine (LDAC) for newly diagnosed AML patients not suited for intensive chemotherapy, and will compete with Venclexta in this difficult-to-treat setting. However, in the US, hypomethylating agents are preferred over LDAC, so Venclexta may be preferred over Daurismo.Onureg, an oral formulation of azacitidine, increased overall survival and relapse-free survival in a Phase III trial and was approved in the US as a maintenance therapy following intensive chemotherapy for patients not suited for an HSCT. A European approval decision is expected in mid-2021. The maintenance setting would be a new setting for Vidaza (azacitidine) which is currently used in the EU (and off-label in the US) to treat newly diagnosed elderly AML patients.Rafael Pharmaceuticals is developing devimistat (CPI-613) as a first-in-class therapeutic targeting the altered mitochondrial metabolism present in many cancers, including AML. Devimistat's outlook will depend on the efficacy and safety results from a Phase III trial evaluating the drug in combination with high-dose cytarabine and mitoxantrone in relapsed/refractory AML patients. The first interim analysis is expected in Q2 2021.Chimerix's dociparstat sodium (DSTAT), a glycosaminoglycan analog of heparin designed to have reduced anticoagulant effects, targets the CXCR4 pathway which is involved in the homing and adhesion of AML cells to the bone marrow and is associated with resistance to systemic drugs. DSTAT is being developed in combination with intensive 7+3 chemotherapy for newly diagnosed AML, with the aim of improving the rate of durable response. A Phase III trial is enrolling patients with intermediate or unfavorable cytogenetic risk (74% of patients eligible for intensive chemotherapy).Otsuka's Inqovi is an oral formulation of decitabine that is being developed for patients with AML unsuited for intensive induction chemotherapy. In ASCERTAIN, a Phase III trial enrolling patients with MDS, Inqovi met the trial's primary endpoint of demonstrating pharmacokinetic equivalence to intravenous decitabine. ASCERTAIN has now been extended to include patients with AML in the EU, but a trial with efficacy endpoints will be needed to secure a US AML approval.Takeda's pevonedistat targets the NEDD8-activating enzyme in the ubiquitin-proteasome pathway, and is being developed in combination with azacitidine for a subpopulation of newly diagnosed, elderly AML patients categorized as low-blast count AML. Pevonedistat is also being evaluated in a randomized Phase II trial in combination with Venclexta and azacitidine in newly diagnosed AML patients unfit for intensive chemotherapy.Zeltherva is a therapeutic vaccine being developed as maintenance therapy for patients who have achieved hematologic complete remission, with or without thrombocytopenia, after second-line therapy and who are ineligible for allogeneic stem cell transplantation. Zeltherva's outlook in the specialized setting of CR2 will depend on results in REGAL, its Phase III trial. An interim analysis for safety and futility is expected in Q4 2021.Not including FLT3 and IDH inhibitors, there are five drugs in late-phase development for newly diagnosed AML patients. Dociparstat sodium and entospletinib are being developed in combination with intensive chemotherapy, while MBG453, pevonedistat, and Inqovi are being developed for elderly patients.Relapsed/refractory AML remains an area of unmet need, and new therapies are being developed. Not including FLT3 or IDH inhibitors, there are currently five late-stage therapies being evaluated for this setting (devimistat, DFP-10917, flotetuzumab, Iomab-B, and uproleselan).Key recent events include the approval of Onureg and presentation of numerical data from Venclexta's VIALE-A trial. There were Phase III failures for Helsinn's pracinostat combined with azacitidine in the newly diagnosed setting and for Roche's idasanutlin and Otsuka's guadecitabine in the relapsed/refractory setting. Other Phase III failures include trials evaluting Xospata combined with azacitidine and Daurismo combined with intensive chemotherapy in front-line AML, and an Idhifa monotherapy trial in the third- and fourth-line setting.Key upcoming catalysts for 2021 include topline results from Phase III trials for devimistat, Iomab-B, uproleselan, and Zeltherva, and a possible NDA submission for FT-2102.The overall likelihood of approval of a Phase I AML asset is 6.3%, and the average probability a drug advances from Phase III is 50%. AML drugs, on average, take 10.8 years from Phase I to approval, compared to 9.6 years in the overall oncology space. Companies Mentioned For more information about this report visit