【Drug News】2017年12月药物快讯 - 科睿唯安
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【Drug News】2017年12月药物快讯
新药评审 & 特殊资格认定
日，FDA批准trastuzumab的生物类似药Ogivri上市
FDA日前批准了美兰公司（Mylan）的Ogivri（trastuzumab-dkst）作为罗氏的重磅炸弹药物赫赛汀（Herceptin, trastuzumab）的生物仿制药上市，用于治疗HER2基因过表达的乳腺癌及转移性胃癌（胃或食管胃交界部腺癌）。Ogivri由Mylan公司和Biocon公司共同开发，是美国批准的针对这两种特定癌症的第一款生物类似药，也是用于癌症治疗的第二款生物类似药。（FDA新闻稿；Mylan公司新闻稿）。
Dec 04, 2017, FDA approves trastuzumabbiosimilarOgivri
The FDA has given Mylan the go-ahead for its Ogivri (trastuzumab-dkst), a biosimilar to Roche’s blockbuster breast cancer therapy Herceptin (trastuzumab), for patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene. Codeveloped with Biocon, Ogivri represents the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second approved in the U.S. for cancer, regulators noted (FDA News R Mylan News Release).
日，FDA授予Arog Pharmaceutical的crenolanib快速通道权限
Arog Pharmaceuticals宣布FDA授予了旗下药物crenolanib的快速通道权限。这是一个口服的苯并咪唑类激酶抑制剂，用与治疗带有FLT3阳性突变的复发或难治性急性髓系白血病（AML）。目前该公司正在准备该药的临床III期研究，将招募FLT3阳性突变的复发或难治性AML患者进行联合最佳支持治疗的、有安慰剂对比的临床试验。（Arog Pharmaceuticals公司新闻稿）。
图为Crenolanib besylate结构
Dec 04, 2017, FDA grants fast track designation to Arog Pharmaceuticals’ crenolanib
Arog Pharmaceuticals said the FDA granted fast track designation to crenolanib, an oral benzimidazole type I kinase inhibitor, for the treatment of patients with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML). The company is preparing to run a phase III trial comparing crenolanib to placebo, both in combination with best supportive care, in patients with FLT3 mutation-positive relapsed or refractory AML (Arog Pharmaceuticals News Release).
日，FDA批准诺和诺德公司的Ozempic用于治疗2型糖尿病
诺和诺德公司宣布FDA批准了其新药Ozempic（semaglutide，0.5mg/1.0mg注射液）上市，用于治疗2型糖尿病。该药为每周一剂的GLP-1受体激动剂，用于配合饮食和运动改善患者的血糖控制。本次批准是基于一项IIIa期临床试验的结果，数据表明用药组的糖化血红蛋白（A1c）水平对比多个对照组（安慰剂、西他列汀和艾塞那肽缓释剂）均有显著性的统计学意义的下降。（诺和诺德公司新闻稿）。
图为Semaglutide结构
Dec 07, 2017, FDA approves Novo Nordisk’s Ozempic for type 2 diabetes
Novo Nordisk said the FDA approved its NDA for Ozempic (semaglutide) injection 0.5 or 1 mg, a once-weekly glucagon-like peptide (GLP-1) receptor agonist, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Approval was based on data from the phase IIIa trial, in which type 2 diabetes patients showed clinically meaningful and statistically significant reductions in A1c with Ozempic treatment compared with placebo, sitagliptin and exenatide extended-release (Novo Nordisk News Release).
日，FDA授予卵巢癌维持治疗的新药rucaparib优先审评资格
FDA接受了Clovis Oncology公司关于rucaparib（Rubraca）的补充NDA申请，并根据处方药使用者费用法案（PDUFA）授予其优先审评资格（限期至日）。该药将用于对铂化疗敏感的复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌患者的维持治疗，且不依赖于患者的BRCA突变，不需要进行诊断性检测。该项补充NDA申请基于一项名为ARIEL3的双盲、有安慰剂对照的Ⅲ期临床试验，共招募了564例重度上皮性卵巢癌、输卵管癌或原发性腹膜癌受试者（ClinicalTrials.gov编号NCT）。初步的疗效评价将在三个预先设定好的分组中逐层进行，分别是BRCA突变组、HRD阳性组和意向治疗人群组。Clovis在去年6月已经公布了先期的积极结果。Rubraca已在美国通过加速审评获批作为单药疗法用于治疗携带有害BRCA突变（生殖细胞和/或体细胞）且已使用两种或多种化疗药物治疗过的晚期卵巢癌患者，其基因突变可由FDA 批准的伴随诊断检测确定。在欧洲，Clovis计划在今年初向提交一份MAA变更用于该维持治疗适应症，这取决于EMA是否会批准其卵巢癌适应症。EMA的人用药物委员会（CHMP）预计将在本月底公布对该药用于卵巢癌治疗适应症的审评意见（Clovis公司新闻稿）。
图为Rucaparib结构
Dec 07, 2017, FDA grants priority review for rucaparibsNDA for maintenance therapy in ovarian cancer
The FDA has accepted Clovis Oncology’s supplemental NDA (sNDA) for rucaparibcamsylate and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of April 6, 2018. Clovis is seeking approval of rucaparib as maintenance treatment in patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are platinum sensitive, and in a complete or partial response to platinum-based chemotherapy, regardless of a patient’s BRCA mutation status. There is no requirement for diagnostic testing. The sNDA is based on data from the double-blind, placebo-controlled phase III ARIEL3 trial in 564 women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer (ClinicalTrials.gov Identifier NCT). The primary efficacy analysis evaluated three prospectively defined molecular sub-groups in a step-down manner: 1) BRCA mutant 2) HRD- and 3) the intent-to-treat population. Clovis announced promising topline results in June. In the U.S., Rubraca is already approved (accelerated approval) as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer, who have been treated with two or more chemotherapies, and selected for therapy based on an FDA-approved companion diagnostic. In Europe, Clovis intends to file a variation to the MAA early next year for the maintenance indication, contingent on a potential approval in Europe for the ovarian cancer treatment indication. An opinion by the EMA’s Committee for Medicinal Products for Human Use (CHMP) on the ovarian cancer treatment indication is expected late this year (Clovis Oncology News Release).
日，FDA 授予Rhizen公司的RP-6530快速通道权限，用于治疗复发或顽固性的外周T细胞淋巴瘤
FDA 授予Rhizen Pharmaceutical公司的RP-6530（tenalisib）快速通道权限。该药是一种口服、高选择性的PI3K调节亚基抑制剂，可用于治疗复发或顽固性的外周T细胞淋巴瘤（PTCL）。除了抑制肿瘤细胞和原发性白血病细胞的生长，RP-6530还能在临床用药浓度下对肿瘤的微环境起到重要的调节作用。在临床前研究中，RP-6530可将巨噬细胞从免疫抑制的M2表型（肿瘤进展）转化为一种炎症性M1样状态（抗肿瘤），或能增强检测点抑制剂的活性或克服药物的耐药性。（Rhizen Pharmaceuticals新闻稿）
图为Tenalisib结构
Dec 11, 2017, FDA grants fast track designation to Rhizen’s RP-6530 for relapsed/refractory PTCL
The FDA has granted fast track designation to RP-6530 (tenalisib), Rhizen Pharmaceuticals’ highly selective and orally active dual phosphatidylinositol 3-kinase (PI3K) regulatory subunit delta/gamma inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Besides inhibiting growth of immortalized cancerous cell lines and primary patient leukemic/lymphoma cells, RP-6530 plays a significant role in modulation of tumor microenvironment at clinically achievable concentrations. In preclinical studies, RP-6530 reprograms macrophages from an immunosuppressive M2-like phenotype (pro-tumor) to an inflammatory M1-like state (antitumor), which can potentially enhance the activity of checkpoint inhibitors or overcome resistance to these drugs (Rhizen Pharmaceuticals News Release).
抗肿瘤药物
日，Mirati Therapeutics公司和Array BioPharma公司发表结构新颖的KRAS突变体抑制剂
Mirati Therapeutics公司和Array BioPharma公司近日发表了一类全新结构的KRAS突变体 （Gly12Cys）抑制剂，有望应用于癌症，尤其是非小细胞肺癌的治疗。其中一个代表化合物可以诱导KRAS G12C 蛋白进行共价修饰。该化合物在KRAS G12C 介导的ERK（Thr202/Tyr204）磷酸化筛选模型中能够抑制携带KRAS G12C突变的人肺癌细胞NCI-H358的增值（IC50 = 0.001-1 mcM）。（详见专利WO ）。
图为专利WO 中的代表化合物
Dec 05, 2017, Mirati Therapeutics and Array BioPharma describe new mutant KRAS inhibitors
Mirati Therapeutics and Array BioPharma have presented novel KRAS (Gly12Cys mutant) inhibitors reported to be useful for the treatment of cancer, in particular non-small cell lung cancer. An exemplified compound induced covalent modification in KRAS G12C protein. It inhibited proliferation of human lung NCI-H358 cancer cells expressing KRAS G12C (IC50 = 0.001-1 mcM) in KRAS G12C-mediated ERK (Thr202/Tyr204) phosphorylation assays (WO ).
日，Genentech公司和Constellation 公司发表结构新颖的CBP抑制剂
Genentech公司和Constellation 公司发表了一类结构新颖的CREB结合蛋白（CBP）抑制剂，有望 应用于癌症、炎症和自身免疫性疾病的治疗。其中一个代表化合物在TR-FRET荧光检测中表现出对CBP的高抑制活性（IC50 = 0.004 mc）。（详见专利WO ）。
图为专利WO 中的代表化合物
Dec 11, 2017, Novel CBP inhibitors presented by Genentech and Constellation Pharmaceuticals
Genentech and Constellation Pharmaceuticals have disclosed new CREB-binding protein (CBP) inhibitorsreported to be useful for the treatment of cancer, inflammation and autoimmune disease. An exemplified compound inhibited CBP activity (IC50 = 0.004 mcM) in TR-FRET assays (WO ).
日，INCB-057643在晚期肿瘤患者的临床试验中显示了乐观的初步结果
Incytes公司披露了其溴结构域及超末端结构蛋白（BET）抑制剂INCB-057643用于治疗晚期癌症的临床I/II试验的初步研究结果，包括一组剂量爬坡试验后进一步的剂量扩大试验，分别有21名和40名受试者参加（ClinicalTrials.gov编号NCT）。在第一阶段试验中，给药剂量分别为每天一次8，12和16 mg，由于最高剂量的耐受性不佳，遂确定以12mg作为第二阶段试验的给药剂量。INCB-057643具有良好的毒理安全性，依剂量增加会产生的主要不良反应包括食欲减退、恶心、高血糖、血小板减少、精神障碍、疲劳和腹泻。其中两位滤泡淋巴瘤受试者分别出现了对药物的完全应答和部分应答。该药的口服平均半衰期为12-14小时并具有适中的清除率。该药在代谢过程中会造成c-MYC的表达量降低。这项临床研究仍在进行中，并已经扩大为与其他药物的联合用药研究。（Forero-Torres, A. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 4048）。
Dec 12, 2017, Favorable initial results seen with INCB-057643 in patients with advanced cancer
Preliminary results have been reported from a phase I/II of Incytes’ inhibitor of bromodomain and extra-terminal motif (BET) proteins INCB-057643 in patients with advanced malignancies. A dose-escalation phase was followed by a dose-expansion phase, with 21 and 40 patients, respectively (ClinicalTrials.gov Identifier NCT). In the first phase, doses of 8, 12 and 16 mg q.d. were evaluated, with the highest dose found to be not tolerated and the 12-mg dose selected for the second phase. INCB-057643 displayed tolerable safety, with increased international normalized ratio the only dose-limiting toxicity and decreased appetite, nausea, hyperglycemia, thrombocytopenia, dysgeusia, fatigue and diarrhea among the most common treatment-related adverse events. One patient had a complete response and another had a partial response (both with follicular lymphoma). The mean t1/2 was approximately 12-14 hours and interpatient variability in oral clearance was moderate. Pharmacokinetics were correlated with reduced c-MYC expression. The study is ongoing and has been expanded to evaluate INCB-057643 in combination with other agents (Forero-Torres, A. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 4048).
日，乳腺癌新药GDC-0927的I期临床结果被披露
基因泰克公司在圣安东尼奥乳腺癌论坛上公布了首个选择性口服的雌激素受体降解剂（SERD）GDC-0927（SRN-927）的I期临床试验数据。该药表现出了良好的耐受性和临床效果。这项开放标签的剂量爬坡和剂量扩大研究招募了患有HER2阴性且雌激素受体阳性的、已绝经的转移性乳腺癌女性患者参与，并分组进行了剂量为600mg（n = 3），1000mg（n = 3）或1400mg（n = 36）的剂量爬坡试验。在三个组别中，分别有100%，100%和72%的受试者由于疾病进展中止了研究。安全性数据显示该药没有剂量依赖的毒性反应，也没有与药物有关的严重、三级或以上的不良事件发生。轻度恶心是最主要的副作用（n = 11；26%），其中8人（19%）与服用该药相关。有1例中度恶心但被认为与服用该药无关。其余的一级或二级不良反应主要包括腹泻（n = 8），便秘（n = 7），疲劳、潮热、呕吐（n = 6），腹痛、贫血、关节痛和天冬氨酸转氨酶升高（n = 3）。其他与药物有关的不良事件包括衰弱、头痛、肌肉骨骼疼痛、食欲下降（n = 1）、肢体疼痛（n = 2）和肌肉痛（n = 3）。在1400mg剂量组，有2名患者由于恶心、呕吐和眩晕而中断过治疗。由于没有达到最高耐受剂量，所以1400mg被推荐作为临床II期试验的用药剂量。在药代动力学性质方面，GDC-0927表现出剂量依赖的血浆暴露量升高，半衰期约为20小时，支持每日服用一剂。其平均的累积率约为1.6， Cmax和AUC2的变异系数（CV）分别为60%和50%。药效学数据显示，在受试者的组织检测中，ESR1突变患者的ER/PR水平和肿瘤细胞增殖均出现下降。患者服药后接受FES-PET影像检查显示对FES的摄取率出现了完全或90%以上的抑制。在1400mg剂量组，GDC-0927未经确认的整体应答率为13%（n = 3/24），临床受益率为36%（n =13/36），这些临床受益主要来自曾接受过fluvestrant或CKD4/6抑制剂治疗的患者和携带ESR1突变的患者。循环肿瘤DNA（ctDNA）检测发现，大部分ESR1突变的临床受益患者的突变等位基因频率出现了降低；在6名患者中（n = 6/19）出现了ESR1突变的ctDNA升高，但未发现与任何一种突变相关联。（Dickler, M.N. et al. 40th Annu San Antonio Breast Cancer Symp (Dec 5-9, San Antonio) 2017, Abst PD5-10）。
Dec 13, 2017, First phase I data reported for GDC-0927 in breast cancer
Data from a first-in-human phase I study of the selective oral estrogen receptor degrader (SERD) GDC-0927 (SRN-927; Genentech) were presented at the San Antonio Breast Cancer Symposium. The drug was well tolerated, with encouraging clinical benefit seen. The open-label, dose-escalation and expansion study enrolled postmenopausal women with estrogen receptor-positive (ER+), HER2-negative metastatic breast cancer who received escalating doses of 600 (n = 3), 1000 (n = 3) or 1400 mg (n = 36). Of these patients, 100%, 100% and 72%, respectively, discontinued due to disease progression. Safety data showed no dose-limiting toxicities and no serious or grade 3 or above adverse events were noted to be related to the drug. Grade 1 nausea was the main adverse event (n = 11; 26%), of which 8 (19%) were considered there was 1 case of grade 2 nausea but this was not related to the drug. Other common grade 1 or 2 adverse events were diarrhea (n = 8), constipation (n = 7), fatigue, hot flush, vomiting (n = 6 each), abdominal pain, anemia, arthralgia and increased aspartate aminotransferase (n = 3 each). Other adverse events (grade 1) related to the drug included asthenia, headache, musculoskeletal pain, decreased appetite (n = 1 each), pain in extremity (n = 2) and myalgia (n = 3). At the 1400 mg dose 2 patients required treatment interruption due to grade 1 nausea, vomiting and vertigo. The maximum tolerated dose was not reached and the recommended phase II dose was 1400 mg. In terms of pharmacokinetics, plasma exposures of GDC-0927 increased dose-dependently, with an estimated half-life of approximately 20 h, allowing for daily dosing. The mean accumulation ratio was approximately 1.6-fold, and 60% variability (CV) with Cmax and approximately 50% CV with AUC24 was seen at steady state with 1400 mg. Pharmacodynamic data showed evidence of reduced ER/PR levels and proliferation was seen with on-treatment biopsies, including patients with ESR1 mutations. Patients with FES-PET and avid disease at baseline showed complete or & 90% suppression of FES uptake to background levels post-GDC-0927. With the 1400 mg dose there was a 13% unconfirmed overall response rate with GDC-0927 (n = 3/24 patients with RECIST measurable disease) and a 36% clinical benefit rate (n =13/36). Clinical benefit was seen in patients with prior fluvestrant/CKD4/6inhibitor treatment or ESR1 mutations. As measured by circulating tumor DNA (ctDNA), most patients with clinical benefit and ESR1 mutant tumors had decreased mutant allele frequency, and increased ESR1 mutant ctDNA (n = 6/19) was seen across a range of mutations without association with any particular one (Dickler, M.N. et al. 40th Annu San Antonio Breast Cancer Symp (Dec 5-9, San Antonio) 2017, Abst PD5-10).
日，Pharmaxis公司的赖氨酰氧化酶抑制剂在原发性骨髓纤维化模型中显示有效
Pharmaxis公司的赖氨酰氧化酶抑制剂PXS-5446在原发性骨髓纤维化的GATA1低表达小鼠模型中显示了潜在作用。PXS-5446共进行了为期10周，每周4次，每次15 mg/kg剂量的给药，结果显示其小鼠耐受性良好。给药组小鼠的脾脏重量明显低于对照组，且血小板计数明显降低，而血红蛋白数量未受影响。给药组小鼠的骨髓纤维化和脾脏纤维化（只在雄性小鼠中）与对照组相比明显减少。给药组小鼠的骨髓巨核细胞与脾巨核细胞染色呈下降趋势，在雄性动物中更加显著。上述发现为PXS-5446用于治疗原发性骨髓纤维化的机制研究奠定了基础。（Leiva, O. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 4214）。
Dec 18, 2017, Lysyl oxidase inhibitor from Pharmaxis shows promise in model of primary myelofibrosis
The promise of lysyl oxidase inhibition in treating primary myelofibrosis has been investigated at Pharmaxis using the novel inhibitor PXS-5446 in GATA1-low mice, a model of the condition. PXS-5446 was well tolerated in GATA1-low mice when given at a dose of 15 mg/kg four times per week for 10 weeks. Animals given PXS-5446 has significantly lower spleen weights compared to vehicle-treated animals, as well as significantly lower platelet counts after treatment, while hemoglobin was unaffected. Bone marrow fibrosis was significantly reduced in mice given PXS-5446, as was splenic fibrosis (in male mice only), compared to vehicle. Staining for bone marrow megakaryocytes was decreased in the PXS-5446 group, as was splenic megakaryocytes, though more so in male than female animals. The findings encourage further development of PXS-5446 and this mechanism of action in primary myelofibrosis (Leiva, O. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 4214).
日，化合物ICEC-0942能在临床前乳腺癌模型中抑制肿瘤生长
来自伦敦帝国理工学院的研究者发表了一个全新结构的口服CDK7小分子抑制剂ICEC-0942用于雌激素受体（ER）阴性或阳性的乳腺癌治疗的实验数据。ICEC-0942是从1000多个化合物中筛选得到的，它对CDK7的抑制活性为IC50=40 nM。体外实验证实ICEC-0942可通过抑制包括CDK1，CDK2和RNA聚合酶II的磷酸化在内的CDK7靶标来抑制激素受体阳性和三阴乳腺癌细胞的增殖（GI50 = 0.2 &# mcM）。在体内试验中，日剂量100 mg/kg的ICEC-0942能够抑制MCF7异种移植动物的肿瘤生长并为表现出毒性反应。ICEC-0942与他莫昔芬联用可以完全阻断雌激素受体阳性的乳腺癌异种移植动物的肿瘤生长。此外，该化合物具备良好的药代动力学性质，有望开发成为抗肿瘤口服新药。（Ali, S. et al. 40th Annu San Antonio Breast Cancer Symp (Dec 5-9, San Antonio) 2017, Abst P1-10-05）。
图为ICEC-0942结构
Dec 22, 2017 , ICEC-0942 reduces tumor growth in preclinical models of breast cancer
Researchers from Imperial College London presented data for ICEC-0942, a novel oral selective inhibitor of the cell cycle and transcriptional regulator cyclin-dependent kinase 7 (CDK7), being developed for the treatment of estrogen receptor (ER)-positive and -negative breast cancer. Screening of more than 1,000 analogues resulted in the development of a clinical candidate CDK7 inhibitor, ICEC-0942, which selectively inhibited CDK7 with an IC50 of 40 nM. In vitro analyses revealed that ICEC-0942 inhibited the growth of hormone receptor-positive and triple-negative breast cancer cell lines (GI50 = 0.2 &# mcM), accompanied by inhibition of CDK7 targets, including CDK1, CDK2 and RNA polymerase II phosphorylation. In vivo, ICEC- mg/kg/day) inhibited tumor growth in MCF7 tumor xenografts, demonstrating substantial antitumor effects and a notable lack of toxicity. In the combination setting with tamoxifen, ICEC-0942 completely blocked the growth of ER-positive tumor xenografts, suggesting the potential for co-treatment with hormonal agents. Extensive ADMET, pharmacokinetic and pharmacodynamic studies confirmed oral bioavailability and the suitability of ICEC-0942 as a cancer drug (Ali, S. et al. 40th Annu San Antonio Breast Cancer Symp (Dec 5-9, San Antonio) 2017, Abst P1-10-05).
日，WHSC1或可作为治疗急性淋巴细胞白血病的靶标
儿童急性淋巴细胞白血病（ALL）在所有儿科癌症中占据25%，是儿科最频发的癌症之一。其中有约20%的ALL对现有疗法没有响应，这导致了很高的致死率。一个来自加拿大的研究团队希望能寻找新的治疗靶点来解决上述问题。他们对200名儿科ALL患者进行了外显子组测序，试图确定与患病高度相关的基因突变。在发现的132个候选基因中，进一步通过细胞实验确定了一个名为WHSC1的组蛋白-赖氨酸-N端甲基转移酶（NSD2）的潜在靶标。共有8名患者（4%）携带有NSD2突变，且全部为E1099K突变体。此外还发现化合物MCTP-39可作为WHSC1的抑制剂，但从未被用于ALL的治疗。细胞活性测试数据显示，MCTP-39对WHSC1野生型细胞的抑制活性为0.867 &# mcM，对E1099K突变体的抑制活性为0.885 mcM。进一步发现给予不同剂量的MCTP-39（0.125, 0.25, 0.5, 1.0 and 2.0 mcM）5天以后，E1099K突变体细胞对该化合物的作用比野生型细胞更加敏感。上述结论显示，WHSC1有望作为治疗儿童急性淋巴细胞白血病的新靶点。（Khoury, H. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 2072）。
Dec 27, 2017, WHSC1 revealed as a promising therapeutic target for ALL
Childhood acute lymphoblastic leukemia (ALL) is one of the most frequent pediatric cancers, accounting for about 25% of all pediatric cancers. Approximately 20% of these tumors do not respond to therapy, leading to a high rate of mortality among these patients. Researchers from Canada conducted a study with the aim of finding new therapeutic targets to face this problem. Whole exome sequencing was performed of matched tumor and normal DNA from 200 pediatric ALL patients to identify genetic mutations. The results revealed 132 candidate genes, which were further validated in cell lines and from which WHSC1, also known as histone-lysine N-methyltransferase NSD2, was identified. Eight out of the 200 patients (4%) harbored a mutation in the NSD2 gene, with all of these mutations involving an amino acid change at position 1099 from glutamic acid to lysine (p.E1099K). On the other hand, MCTP-39 has been identified as inhibitor of WHSC1, but never tested in ALL. When tested in ALL cell lines, it showed IC50 values ranging from 0.867 to 2.543 mcM in WHSC1 wild-type cell lines, and with an IC50 value of 0.885 in a cell line that was E1099K mutant. After treatment of cell lines with single MCTP-39 doses (0.125, 0.25, 0.5, 1.0 and 2.0 mcM) for 5 days, the E1099K-mutant cell line (RS411) showed higher sensitivity to MCTP-39 than wild-type cell lines. These results unveil WHSC1 as a novel promising therapeutic target for treating ALL in children (Khoury, H. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 2072).
抗肿瘤免疫疗法
日，佛罗里达大学发现新的抗TSHR嵌合抗原受体
佛罗里达大学发现了新的靶向甲状腺特异性激素受体（TSHR）的嵌合抗原受体（CARs），它包含一段抗原识别区域，一段跨膜区域和一段包含凋亡诱导因子的细胞质区域，有望用来治疗甲状腺癌，尤其是分化型、乳头状和滤泡性甲状腺癌。构建的模板细胞为激活的人体T细胞通过密码子优化的第四代CARs转导，包含一个靶向TSHR的人源化单链可变区（scFv）、一段CD28跨膜域、一段41BB共刺激域（CD137）、一段CD27细胞质和CD3zeta细胞信号域、一段2A肽序列和诱导凋亡的Caspase-9（iCasp9）。经细胞毒实验确定，将其与人甲状腺乳头状癌K-1细胞和人滤泡性甲状腺癌FTC-133细胞一同培养后可诱导肿瘤细胞的裂解。此外，它还能在K-1和FTC-133细胞中分别将与细胞凋亡相关的caspase 3/7表达量上调38.1%和94.2%。（详见WO ）。
Dec 07, 2017, Novel anti-TSHR chimeric antigen receptors identified at the University of Florida
The University of Florida has presented new chimeric antigen receptors (CARs) comprising an antigen binding domain targeting thyroid specific hormone receptor (TSHR), a transmembrane domain and cytoplasmic domains comprising an inducible trigger of apoptosis, claimed to be potentially useful for the treatment of thyroid cancer, especially differentiated, papillary and follicular thyroid cancer. Exemplary cells were activated human T cells transduced with codon-optimized, fourth-generation CARs comprising a humanized single chain variable fragment (scFv) targeting TSHR, a CD28 transmembrane domain, a 41BB co-stimulatory domain (CD137), a CD27 cytoplasmic and CD3zeta intacellular signaling domain, a 2A peptide sequence and inducible suicide gene Caspase-9 (iCasp9). The selected product cocultured with human thyroid papillary carcinoma K-1 cells and human follicular thyroid carcinoma FTC-133 cells induced cell lysis, as determined by cytotoxicity assay. Furthermore, the selected product increased caspase 3/7 expression (involved in cell apoptosis) by 38.1% and 94.2% in K-1 and FTC-133 cells, respectively, as estimated by caspase-glo 3/7 assay (WO ).
日，Incyte公司发现了新颖的PD-1信号抑制剂
Incyte公司发现了一类可作为PD-1信号抑制剂的杂环化合物，有望用于治疗癌症和病毒感染。其中一个代表化合物在HTRF 荧光结合实验中表现出对重组人PD-1与配体PD-L1结合的抑制活性（IC50 = 100 nM or less）。（详见专利WO ）。
图为专利WO 中的代表化合物
Dec 12, 2017, Novel PD-1 signaling inhibitors presented by Incyte
Incyte has divulged heterocyclic compounds acting as programmed cell death protein 1 (PD-1) signaling inhibitors reported to be useful for the treatment of cancer and viral infections. An exemplified compound inhibited recombinant human PD-1 interaction with its ligand PD-L1 (IC50 = 100 nM or less) in homogenous-time resolved fluorescence (HTRF) binding assays (WO ).
心血管疾病
日，Enanta Pharmaceuticals公司发表新结构的胆酸受体激动剂
Enanta Pharmaceuticals公司发现了一类结构新颖的异恶唑类化合物作为胆酸受体（BAR）激动剂，有望用于治疗肾脏、肝脏、心血管、胃肠道和代谢类疾病。其中一个代表化合物在反式激活实验中在CHO细胞上显示了对人源BAR的激动活性（EC50 = 0.1-1 mcM, efficacy = 279%）。（详见WO ）。
图为专利WO 中的代表化合物
Dec 11, 2017, Enanta Pharmaceuticals discovers bile acid receptor agonists
Enanta Pharmaceuticals has identified novel isoxazole analogues acting as bile acid receptor (BAR) agonistsreported to be useful for the treatment of renal, liver, cardiovascular, gastrointestinal and metabolic disorders. An exemplified compound displayed agonist activity at human BAR expressed in CHO cells (EC50 = 0.1-1 mcM, efficacy = 279%) in transactivation assays (WO ).
日，Akarna Therapeutics公司发表新结构的BAR激动剂
Akarna Therapeutics公司发现了结构新颖的并杂环类化合物作为胆酸受体（BAR）激动剂并申请了专利，该类化合物有望用于治疗动脉粥样硬化、糖尿病、血脂异常、原发性胆汁性肝硬化、胆汁淤积、代谢综合征、非酒精性脂肪肝和肥胖。其中一个代表化合物在荧光素酶测试中表现出胆酸受体的激动活性（EC50 & 200 nM）。（详见专利WO ）。
图为专利WO 中的代表化合物
Dec 13, 2017 , Akarna Therapeutics presents novel BAR agonists
Akarna Therapeutics has patented fused bicyclic compounds acting as bile acid receptor (BAR) agonists reported to be useful for the treatment of atherosclerosis, diabetes, dyslipidemia, primary biliary cirrhosis, cholestasis, syndrome X (metabolic syndrome), nonalcoholic steatohepatitis and obesity, among others. An exemplified compound displayed agonistic activity against BAR (EC50 & 200 nM) in Gaussia luciferase flash assays (WO ).
代谢类疾病
日，Burosumab在治疗X染色体遗传性低磷血性佝偻病的III期临床试验中表现出乐观数据
Ultragenyx Pharmaceutical公司和Kyowa Hakko Kirin公司日前报道了Burosumab（KRN-23）在治疗X染色体遗传性低磷血性佝偻病的III期临床试验中的数据。Burosumab是一个靶向高磷尿激素成纤维细胞生长因子23的抗体。数据显示，在接受治疗后的48周，患者的血清磷水平可持续保持正常，并在最初的24周治疗后改善了身体僵硬、疼痛等病症，恢复了身体机能。对于前24周接受安慰剂治疗的患者，在改用Burosumab治疗以后，上述症状同样得到了改善，血清磷水平也恢复了正常。此外，Burosumab还能够加快骨折的愈合。（Ultragenyx Pharmaceutical公司新闻稿）。
Dec 05, 2017, Burosumab shows positive results in phase III study in X-linked hypophosphatemia
Ultragenyx Pharmaceutical and Kyowa Hakko Kirin have reported data from a phase III trial testing burosumab(KRN-23), an antibody targeting the phosphaturic hormone fibroblast growth factor 23, in adults with X-linked hypophosphatemia. Patients treated with burosumab for 48 weeks continued to have normal serum phosphorus levels and experienced further improvement in stiffness, physical function and pain from the initial 24 week treatment. The patients who crossed over from placebo to burosumab after 24 weeks showed normalization of serum phosphorus and improvement in stiffness, pain and physical functioning. Burosumab also increased the rate of fracture healing (Ultragenyx Pharmaceutical News Release).
日，化合物MGL-3196在治疗非酒精性脂肪肝的II期临床试验中达到首要临床终点
Madrigal Pharmaceuticals公司日前发布了令人鼓舞的消息，其临床候选药物MGL-3196在治疗经活检确诊的非酒精性脂肪肝的II期概念验证性临床试验中达到首要临床终点（ClinicalTrials.gov编号NCT）。MGL-3196是一个原创的每日一剂的口服且可直接作用于肝脏的甲状腺激素受体beta选择性激动剂。在该项研究中，MGL-3196的主要终点为磁共振成像方法（MRI-PDFF）测量的肝脂肪比例与安慰剂相比的变化百分比，目前显示其结果已具有统计学意义。数据显示，用MRI-PDFF测量的肝脏脂肪减少了30%以上，且与肝活检显示的NASH症状改善相关，患者的ALT和AST也出现了显著性降低。在44例用药剂量相对较高的患者中（44/78），ALT和AST的降低与安慰剂相比有更为显著的统计学差异。与安慰剂组相比，多个与NASH有潜在临床相关性的次要终点也表现出了统计学意义的改善，包括LDL-C、甘油三酯、载脂蛋白B和脂蛋白a等。该药的耐受性良好，一些轻微以及中度的不良反应在安慰剂组和治疗组之间的比例是均衡的，对主要的生命体征参数无不良影响。临床中出现的三种严重副作用都被认为与MGL-3196无关。后续的临床试验仍将保持双盲性。在治疗的36周，将会再次通过活检和MRI-PDFF成像方法评价该药的安全性和有效性。在第12周和第36周，将对多种与炎症和纤维化相关的血清生物标志物进行评估。第36周的临床结果预计将在今年第二季度揭晓。（Madrigal Pharmaceuticals公司新闻稿）。
图为MGL-3196结构
Dec 07, 2017, Phase II study of MGL-3196 in NASH meets primary endpoint
Madrigal Pharmaceuticals has announced encouraging topline results from a proof-of-concept phase II trial of MGL-3196, a first-in-class, oral, once-daily, liver-directed, thyroid hormone receptor (THR) beta-selective agonist, in patients with biopsy-proven nonalcoholic steatohepatitis (NASH) (ClinicalTrials.gov Identifier NCT). In this trial, MGL-3196 demonstrated statistically significant results on the primary endpoint, the percent change in hepatic fat versus placebo as measured by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), a non-invasive imaging test. Recently published data have shown a high correlation of the reduction of liver fat of 30% or more as measured by MRI-PDFF to improvement in NASH on liver biopsy. Statistically significant reductions in ALT and AST were observed in MGL-3196 treated patients. Greater reductions in ALT and AST, statistically significant relative to placebo, were observed in the prespecified group of 44/78 patients with relatively higher MGL-3196 drug levels. In drug-treated patients relative to placebo patients, statistically significant improvements were also seen in multiple secondary endpoints considered to be potentially clinically relevant in patients with NASH, including LDL-C, triglycerides, apolipoprotein B (ApoB), and Lp(a). MGL-3196 was well tolerated with mostly mild adverse events, and a few moderate adverse events, the numbers of which are balanced between placebo and drug-treatment groups. There are no adverse effects of MGL-3196 on safety laboratory or vital sign parameters. There have been three serious adverse effects in the study, all considered unrelated to MGL-3196. The ongoing study remains blinded. Safety, efficacy of NASH resolution by biopsy, and repeat MRI-PDFF will be assessed at 36 weeks. Multiple inflammatory and fibrosis serum biomarkers at 12 and 36 weeks are being and will be assessed. Results at 36 weeks are expected in the second quarter of next year (Madrigal Pharmaceuticals News Release).
日，结构新颖的alphaVbeta3拮抗剂有望用于治疗骨质疏松症
在强调了开发整合素alphaVbeta3拮抗剂过程中所涉及的一些挑战后，洛克菲勒大学发表了两个完全拮抗剂TDI-4161和TDI-3761的开发过程，他们可抑制alphav beta3依赖的细胞粘附，而不发生高亲和力的配体结合或MAb AP5抗原表位的暴露（两者都依赖于beta3 PSI结构域）。利用一种对alphaVbeta3具有高亲和力但不会引起beta3结构域摆动的变异纤连蛋白片段hFN10，研究人员开发出了上述两个可直接作用于beta3 Y122残基的小分子hFN10蛋白模拟物。在HEK-293细胞中，化合物TDI-4161和TDI-3761对alphaVbeta3的IC50值分别为22nm和210 nM；与之相比，此前由于效果不佳而终止于临床II期的默克公司的alphaVbeta3拮抗剂MK-0429的IC50值为3.6nm。当MAb AP5的抗原表位暴露后，上述三个化合物的EC50下降至为&10 mcM，&10 mcM和19 nM。体外实验证实TDI-4161可以与beta3 Y122残基直接发生作用，而MK-0429无此作用；同时TDI-4161对1型胶原交联降解肽的抑制率也高于MK-0429。在体内试验中，给予每日一剂的剂量为10，30和100 mg/kg的TDI-4161显示了良好的耐受性，其血浆浓度在第1天到第28天内保持稳定。口服100 mg/kg的TDI-4161后，检测到其Cmax，tmax和半衰期分别为7.5 mcM，0.94小时和3.6小时。TDI-4161和TDI-3761对细胞扩散和骨腔吸收的有明显的抑制作用，且与先前测试的部分激动剂相比，它们对小鼠破骨细胞样细胞的形态影响更小。对于完全拮抗剂是否与先前测试的部分激动剂具有相同的治疗效果，还需进一步的体内研究来评估。（Li, J. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 548）。
上图为TDI-3761结构
上图为TDI-4161结构
Dec 14, 2017, Novel alphaVbeta3 antagonists show promise for osteoporosis
After highlighting some of the challenges involved in developing integrin alphaVbeta3 antagonists, researchers from Rockefeller University discussed the development of two pure antagonists, TDI-4161 and TDI-3761, which inhibited alphaVbeta3-dependent cell adhesion without inducing high-affinity ligand binding or exposure of the epitope for MAb AP5 (both dependent on the beta3 PSI domain). Using a variant fibronectin fragment with high affinity for alphaVbeta3 (hFN10), that did not induce the beta3 swing-out motion, researchers developed small-molecule hFN10 mimics which directly engaged beta3 Y122. In HEK-293 cells, TDI-4161 and TDI-3761 showed an alphaVbeta3 IC50 values of 22 and 210 nM, in comparison the known alphaVbeta3 antagonist MK-0429 (Merck & Co.; c-5889), terminated at phase II due to lack of efficacy, had an IC50 value of 3.6 nM. Exposure of the epitope for MAb AP5 resulted in EC50 values of & 10 mcM, & 10 mcM and 19 nM, respectively. In vitro, TDI-4161 was shown to interact with beta 3 Y122 while MK-0429 did not display the same binding effect and a comparatively greater inhibition of crosslinked collagen type 1 degradation peptide was observed with TDI-4161 than with MK-0429. In vivo, q.d. dosing of TDI-4161 at 10, 30 and 100 mg/kg for 28 days was well tolerated, with plasma levels 1 h post-dosing similar on day 1 and day 28. Oral administration of TDI-4161 at 100 mg/kg, resulted in Cmax, tmax and t1/2 values of 7.5 mcM, 0.94 h and 3.6 h, respectively. TDI-4161 and TDI-3761 showed potent inhibition of cell spreading and bone/lacunae resorption (& 0.05 fraction of bone surface); however, they had less effect on murine osteoclast-like cell morphology than partial agonists previously tested. It was concluded that further in vivo studies were needed to assess whether the pure antagonists have the same therapeutic efficacy as previously tested partial agonists (Li, J. et al. 59th Annu Meet Am SocHematol (Dec 9-12, Atlanta) 2017, Abst 548).
抗感染药物
日，罗氏发现结构新颖的抗HBV小分子化合物
罗氏公司合成了一类含吡嗪结构的化合物，据报道有望用于治疗HBV感染。其中一个代表化合物在定量PCR检测中显示能够在人源肝癌细胞HepG2.2.15中抑制HBV的复制（EC50 = 0.008 mcM）。
图为WO 中代表化合物的结构
Dec 05, 2017, Roche identifies novel compounds for hepatitis B virus infection
Roche has synthesized pyrazine compounds reported to be useful for the treatment of hepatitis B virus (HBV) infection. An exemplified compound inhibited replication of HBV transfected in human liver HepG2.2.15 cancer cells (EC50 = 0.008 mcM) in quantitative PCR assays (WO ).
中枢神经系统疾病
日，利用CRAFT计算模型寻找治疗癫痫的新靶标
来自UCB Pharma公司和伦敦帝国理工学院的研究人员利用计算手段发现了可用来治疗癫痫的新靶点。该方法包括利用与疾病相关的组织的全基因组转录谱分析来识别疾病模式、共同表达的基因和候选调控因子。对于治疗性化合物的系统方法评估不再根据它们与蛋白结合的亲和力，而是根据它们引起转录反应的能力，这与疾病状态下的基础转录能力是反相关的。该方法的因果推理框架（用于靶标发现和因果推理分析框架—“CRAFT”模型）建立了一个具备预测功能的基因组学框架，用于识别对疾病状态有调节作用的膜受体。基于从癫痫模型中获得的海马体全基因组表达数据，CRAFT方法预测到酪氨酸激酶受体Csf1R （巨噬细胞集落刺激因子1受体）可以调节获得性癫痫疾病状态下的炎症，从而有望成为新的治疗靶点。一个Csf1R的小分子抑制剂在两种获得性癫痫模型中表现出抗癫痫作用，其中包括一种药物抵抗性癫痫模型。CRAFT还确定了其他可用于治疗癫痫的候选调节因子并将用于进一步的研究。（Johnson, M.R. et al. 71st Annu Meet Am Epilepsy Soc (Dec 1-5, Washington, D.C.) 2017, Abst 2.002）。
Dec 19, 2017, CRAFT computational approach identifies new targets for treating epilepsy
Scientists from UCB Pharma and Imperial College London with other collaborators have used a computational approach to identify new drug targets for treating epilepsy. The approach consisted of network analysis using genome-wide transcriptional profiling in tissues relevant to the disease to identify modules, or sets of co-expressed genes, as candidate regulators of disease. The systems-level approach assesses therapeutic compounds not according to their binding affinity to a protein but by their ability to induce a transcriptional response anti-correlated to the coordinated transcriptional program underpinning the disease state. The causal reasoning framework employed (causal reasoning analytical framework for target discovery or CRAFT) establishes a predictive functional genomics framework for identifying membrane receptors exerting a regulatory influence over disease states. With genome-wide hippocampal gene expression data from a model of acquired epilepsy, CRAFT predicted the tyrosine kinase receptor Csf1R (macrophage colony-stimulating factor 1 receptor) to regulate an inflammatory module underpinning the acquired epilepsy disease state and therefore to be a novel therapeutic target. A small molecule inhibitor of Csf1R showed antiepileptic efficacy in two models of acquired epilepsy, including a pharmacoresistent model. CRAFT also identified other candidate regulators of acquired epilepsy for possible further investigation (Johnson, M.R. et al. 71st Annu Meet Am Epilepsy Soc (Dec 1-5, Washington, D.C.) 2017, Abst 2.002).}