This is a dose-finding study of oral zelenirstat (PCLX-001) in patients with R/R AML. There are two parts to the study: Dose Escalation and Dose Expansion.

开始日期2024-10-01

申办/合作机构

Pacylex Pharmaceuticals, Inc.

[+1]

NCT04836195 / Recruiting临床1期

Phase I Trial of PCLX-001 in Relapsed/Refractory B-cell Non-Hodgkin Lymphoma and Advanced Solid Malignancies

This is a phase I dose-escalation study of oral PCLX-001, conducted in a multicenter, non-randomized, open-label, non-controlled design. The study is comprised of two parts: Part A (single-agent dose escalation) and Part B (single-agent expansion cohorts).

开始日期2021-09-14

申办/合作机构

Pacylex Pharmaceuticals, Inc.

100 项与 NMT1 x NMT2 相关的临床结果

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100 项与 NMT1 x NMT2 相关的转化医学

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0 项与 NMT1 x NMT2 相关的专利（医药）

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项与 NMT1 x NMT2 相关的文献（医药）

2024-08-01·Investigational New Drugs

A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas

Article

作者: Sehn, Laurie H ; Kuruvilla, John ; Mackey, John R ; Jamal, Rahima ; Spratlin, Jennifer ; Beauchamp, Erwan ; Weickert, Michael ; Sangha, Randeep ; Berthiaume, Luc G

AbstractMyristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.

2023-10-01·International journal of radiation oncology, biology, physics

Radiosensitization of Glioblastoma Using Targeted Inhibition of N-Myristoylation.

Article

作者: Wilson, E ; Dinakaran, D ; Rydzewski, N R ; Camphausen, K A

PURPOSE/OBJECTIVE(S)Treating Glioblastoma remains a major challenge. Radiotherapy has a long-standing role in extending survival, but almost all tumors are expected to recur and be fatal. Historic dose-escalation studies do not yield additional benefit beyond the current 60 Gy dose. Further therapeutic improvement can be gained with radiosensitizers. An undiscovered potential radiosensitization approach may exist in inhibiting the N-myristoylation pathways upregulated in malignant cells. Inhibiting this pathway has been shown to have pleotropic effects including decreasing PARP-1 activity and other cancer-driving pathways that may synergize with radiotherapy. This is a first report in using a targeted N-myristoyltransferase (NMT) inhibitor as a radiosensitizer in glioblastoma.MATERIALS/METHODSImmortalized glioma cell lines (U87 and U251) and patient-derived de novo (ED501) and post-chemoradiation recurrent (ED512) cell lines were used to a NMT1/2 inhibitor with radiotherapy. Cell surface expression levels for NMT1 and NMT2 were established using immunofluorescence microscopy. In vitro cell viability studies via mitochondrial reduction of resazurin dye and clonogenic assays were done with single fraction 2 & 4 Gy irradiation with 5 days of drug exposure (5-150 nM 3 days prior to irradiation and 2 days post) to account for drug pharmacodynamics. PARP-1 expression by western blot was tested with exposure to drug and/or radiation. Whole exome sequencing and methylation profiling were done to find predictive markers of radiosensitization.RESULTSPreliminary results show significant radiosensitization effect with a dose enhancement factor ranging from 1.33 to 2.71x higher than radiation alone. The amount of radiosensitization varied per cell line, with U251 and ED512 being more sensitive. The cell line sensitivity was not reliably predicted by the NMT cell surface receptor expression. PARP-1 activity increased with radiotherapy but was inhibited with drug exposure. Exome sequencing showed the radiosensitizing effect correlated with mutations in DNA damage repair and myristoylation pathways.CONCLUSIONN-myristoylation inhibition appears to be a novel method of radiosensitization for glioblastoma. N-myristoylation affects multiple oncogenic pathways including PARP-1 downregulation, which impedes DNA damage repair and may be what leads to radiosensitization. Future studies are aimed at further predictive markers and in vivo efficacy.

2022-09-01·Lung Cancer

N-mytistoyltransferase 1 and 2 are potential tumor suppressors and novel targets of miR-182 in human non-small cell lung carcinomas

Article

作者: Li, Yuan ; Tang, Erjiang ; Wu, Yazhou ; Goel, Arul ; Xu, Xin ; Cai, Yuchan ; Weng, Wenhao ; Zhang, Tong ; Li, Hanhua ; Zhang, Fanping

BACKGROUND & AIMSNon-small cell lung cancer (NSCLC) accounts for about 80% of lung cancer diagnoses across the world. Despite recent appreciable improvements in treatment plans for patients with NSCLC, the prognosis for those with the cancer still remains poor. Recently, a growing number of studies have shown that N-myristoyltransferases (NMTs) may be critical in carcinogenesis, however, the functional and clinical significance of this pathway in NSCLC remains unclear and requires further research.METHODSInitially, we evaluated the expression levels of NMT1 or NMT2 in a clinical cohort comprising of 303 paired primary NSCLC tissues and matched normal mucosae by using ELISA. We subsequently performed a tissue microarray analysis (TMA) to confirm its expression pattern in an independent validation cohort (n = 78). Then, we used a publicly available KM plotter database (n = 1921) to evaluate the prognostic impact of NMT1 and NMT2 in NSCLC. Lastly, a series of in-vitro molecular/cellular and animal experiments were performed for mechanistic understanding of the role of N-myristoyltransferases in NSCLC.RESULTSOur ELISA data revealed that the expression level of NMT1 and NMT2 was down-regulated in tumor tissues (n = 303, P < 0.0001), which was confirmed in an independent validation cohort by TMA (n = 78, P = 0.014 for NMT1 and P < 0.0001 for NMT2). On the other hand, patients with low expression of NMT1 or NMT2 had shorter overall survival (P = 0.013, HR = 0.85 for NMT1; P = 0.00059, HR = 0.8, for NMT2). Mechanistically, we revealed that the interaction and co-localization of NMT1 and NMT2 in NSCLC, and N-terminus of NMT1 and NMT2 was observed to be crucial for their interaction as well as for their catalytic activity. Moreover, we found that NMT1 can significantly promote the expression of NMT2 by enhancing its stability. We corroborated these findings by performing functional assays in which the knockout of NMT1 and NMT2 resulted in enhanced cell proliferation, migration and invasion as well as increased tumorxenograftgrowth. In addition, we identified miR-182 as a novel regulator of both NMT1 and NMT2. More specifically, the overexpression or inhibition of miR-182 modulated globe N-myristoylation level, contributed to phenotypic alterations in NSCLS cells.CONCLUSIONSNMT1 and NMT2 can act as potential tumor suppressors in NSCLC, and the inhibition of miR-182 expression or therapeutic NMTs replenishment may be a promising treatment option for patients with NSCLC.

项与 NMT1 x NMT2 相关的新闻（医药）

2024-04-19

·药明康德

创新机制蕴含多种抗癌策略！《自然》子刊重磅综述揭露多款潜在靶点

▎药明康德内容团队编辑蛋白质脂化修饰是一种至关重要的翻译后修饰（PTM）机制，这一过程受到40余种酶的精确调控，影响着超过1000种蛋白质底物。这种修饰作用对于细胞信号传导、物质转运和功能的维持发挥着核心作用，同时在调节细胞死亡、维护蛋白质稳定性以及其他基本生物学过程中也扮演着关键角色。在癌症的形成和进展中，蛋白质脂质化尤为关键，涵盖了多个方面，包括调控促进肿瘤生长的癌蛋白功能、调节免疫应答及新陈代谢的核心分子。尽管蛋白质脂化对癌症的影响已经得到了广泛认识，但在药物研发领域，这一机制的研究仍处于初步阶段，既面临挑战也蕴藏着巨大潜力。近期，《自然》杂志子刊Nature Reviews Cancer发表了一篇综述文章，深入分析了蛋白质脂化的生物学基础、在癌症中的异常调控，以及其中的潜在药物靶点。在今天的文章里，药明康德内容团队将为读者展示其中的精彩亮点，分享蛋白质脂化在癌症治疗中的前景。蛋白质脂化在癌症病理过程中的作用蛋白质脂化修饰是一种多样化的PTM机制，在多种生物学活动中扮演着关键角色。这种修饰显著提升了蛋白质分子在脂化位点的疏水性，使得蛋白质与细胞膜之间能够建立直接的物理相互作用，从而深刻影响蛋白质的定位、功能和相互作用。蛋白质脂质化大致可以分为两大类：构成性脂化（constitutive lipidation）和动态脂化（dynamic lipidation）。构成性脂化是蛋白质合成或成熟过程中固有的，脂质基团作为蛋白质不可分割的一部分被添加上去；而动态脂化则根据功能需求在成熟蛋白质上动态添加或移除脂质基团。构成性脂化修饰主要包括S-异戊二烯化（包括法尼基化和香叶基香叶酰化修饰）以及N-豆蔻酰化，而动态脂化中最常见的类型是可逆的S-脂酰化。图片来源：药明康德内容团队制图蛋白质脂化及其在癌症中的角色和治疗潜力是当前生物医学研究中的一个热点领域。作为一种PTM机制，蛋白质脂化在肿瘤的形成、进展和免疫调节中的异常调控揭示了众多未被充分挖掘的潜在药物靶点，为癌症治疗药物的开发带来了新希望。其中，与癌症密切相关的脂化蛋白，特别是关键的脂质转移酶和水解酶，由于它们与多种致癌途径的交互作用，成为了具有重大影响力的潜在治疗靶点。尽管这些酶在癌症中的突变并不普遍，但深入探究它们在致癌基因网络中的作用，可能为发现新的治疗策略提供契机。蛋白质的脂化作用主要发生在细胞内部，这一过程不仅影响蛋白质的分泌和在细胞表面的分布，还可能影响信号传递和抗癌免疫响应。值得注意的是，脂化蛋白也被发现存在于细胞外囊泡中，这一发现为其作为潜在的癌症生物标志物提供了依据。对于某些特定的分泌蛋白，比如Hedgehog和Wnt信号分子，脂化修饰对其旁分泌信号传递至关重要。鉴于完全抑制脂化途径可能产生不利影响，药物开发的策略应侧重于识别能够提供有效治疗且具有良好治疗指数的药物，这些药物可能单独使用或与其他疗法结合，以期获得更优的治疗效果。源自蛋白质脂化过程的新兴抗癌靶点与S-异戊二烯化相关的潜在靶点S-异戊二烯化是一种发生在蛋白质合成后的快速且不可逆的过程，这种修饰持续存在于蛋白质的整个生命周期。这一过程由四种主要的蛋白质异戊二烯化转移酶催化——包括法尼基转移酶（FTase）和三种香叶基香叶酰化转移酶（GGTases I、II和III）。这些酶将异戊二烯基脂质基团附加到蛋白质C末端或其附近的半胱氨酸残基上，从而启动了S-异戊二烯化修饰过程。法尼基转移酶异戊二烯化过程在多种癌症蛋白的调控中扮演了重要角色，尤其是在四种RAS异构体（KRAS4A，KRAS4B，NRAS和HRAS）中。这些RAS蛋白在大约19%的癌症患者中出现突变，通常与治疗耐药性有关。例如，NRAS的激活性突变与黑色素瘤和某些类型的白血病相关联；KRAS突变则普遍见于胰腺癌和肺癌中；HRAS突变则与特定的头颈癌和急性髓系白血病（AML）相关。异戊二烯化通过调节这些癌蛋白的膜定位和信号传导，对它们的功能产生重要影响。针对这些RAS突变及其他异戊二烯化蛋白的治疗策略正在积极研究中。例如，抑制法尼基转移酶可能导致KRAS和NRAS从法尼基化转向由香叶基香叶酰化转移酶I介导的香叶基香叶酰化，这种转变可以恢复RAS蛋白的功能。化学蛋白质组学研究揭示，这种转变仅发生在少数FTase底物，揭示其机制可能有助于发现新的治疗策略和癌症生物标志物。2020年，Zokinvy作为针对蛋白质脂质转移酶的首个药物获得批准，展示了选择性地调节蛋白质脂化修饰来扩大法尼基转移酶抑制剂治疗指数的可能性。此外，由于HRAS蛋白仅通过FTase进行异戊二烯化，FTase抑制剂（FTIs）的使用可以特异性地阻断这一过程。近期研究重点放在使用FTIs治疗带有HRAS突变的头颈部鳞状细胞癌（HNSCC）和AML。此外，FTIs与酪氨酸激酶抑制剂、KRAS G12C抑制剂、PI3Kα抑制剂和EGFR抑制剂等其他靶向药物的联合使用正在探索中，这些联合疗法策略在克服耐药性和防止癌症复发方面显示出潜在的优势，且未观察到显著的毒性。这些研究表明，FTIs可能不仅对RAS异构体，也对其他FTase底物具有治疗潜力。图片来源：123RF靶向异戊二烯生物合成过程抑制异戊二烯生物合成也是一种潜在的癌症治疗策略。他汀类药物通过抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）在胆固醇和异戊二烯生物合成上游发挥作用，但其在癌症治疗中的具体效果还未明确。另一方面，双膦酸类药物（如唑来膦酸）在乳腺癌的辅助治疗中显示出了潜力，这是因为它们能够针对破骨细胞中的异戊二烯二磷酸生物合成过程，从而有助于减少治疗后的转移和复发风险。具有亲脂性的双膦酸类药物具有更广泛的组织分布，并已显示出抑制RAS活性的能力。这类药物与雷帕霉素联用在KRAS驱动的小鼠肺腺癌模型中表现出了治疗效果。因此，进行前瞻性临床试验来明确将异戊二烯生物合成作为癌症一线治疗靶点的可行性是十分必要的。与N-豆蔻酰化相关的潜在靶点N-肉豆蔻酰转移酶（NMT）N-肉豆蔻酰化是一种不可逆的C14:0脂化修饰，由NMT催化，作用于人类蛋白质组中200多种底物蛋白的N-末端甘氨酸上。在哺乳动物中存在两种NMT编码基因，即NMT1和NMT2，这两者在催化区域高度保守。当前研究表明，NMT1在大部分细胞中贡献了超过80%的NMT活性，而NMT2的特异性底物尚未被发现。因此，NMT1被认为是在癌细胞系中的核心必需基因。肉豆蔻酰化作用可促进蛋白质与细胞膜的动态结合，引发诸如S-酰基化等继发性PTM以及蛋白质间的相互作用，影响蛋白质复合体的酶活性或对可溶性蛋白质进行异构调控。NMT活性是癌症治疗中的一个重要干预点，因其能够影响多个难以靶向的癌蛋白。研究显示，抑制NMT可在肿瘤细胞中引发“氨基酸饥饿”反应，阻碍蛋白质合成，这一作用对于蛋白质翻译率较高的癌症尤其有效。此外，NMT抑制剂（NMTi）可能通过抑制ARF和ARL蛋白的功能，在敏感性癌细胞中引发内质网应激，这为多种癌症提供了治疗机会。NMTi通过消除ARF1蛋白肉豆蔻酰化诱导的未折叠蛋白反应（UPR），选择性地清除由化疗或致癌转化产生的衰老细胞。尽管NMT1和NMT2并未直接与癌症相关的突变有关，但研究显示NMT1的表达增加与癌症的进展以及乳腺癌和其他癌症的不良预后有关。目前并未发现NMT2的表达与癌症的严重程度或预后直接相关，虽然在某些血液细胞系和癌症中其表达趋于下降。NMT底物蛋白SRC家族激酶是最早被发现的NMT底物之一。随后的研究揭示，NMT能够调节涉及多个致癌途径的底物蛋白。这些NMT底物包括一些传统上难以作为药物靶点的致癌蛋白家族，例如ADP-核糖化因子蛋白（ARFs）、ARF样蛋白（ARLs），以及参与高尔基体重组与堆积的蛋白（GORASP）。图片来源：药明康德内容团队制图靶向肉豆蔻酰化的其他药理学途径针对豆蔻酰化的药理学策略展示了在癌症治疗领域的新兴途径。例如，BCR-ABL蛋白是伊马替尼的主要作用靶点，然而由于伊马替尼对ABL激酶的选择性不足，导致耐药性和毒性问题，这限制了其临床治疗效果的持续性。Asciminib是一种新型药物，通过靶向BCR-ABL的肉豆蔻酰结合位点，恢复其抑制作用，进而使BCR-ABL失活。2021年，asciminib获得FDA批准，成为首个靶向N-肉豆蔻酰化修饰的药物。此外，选择性诱导铁死亡作为癌症治疗的一个研究热点，展示了肉豆蔻酰化修饰在调节FSP1蛋白相分离中的作用，这种机制可通过药物干预激发铁死亡，对于GPX4功能缺失的黑素瘤和肺癌异种移植模型展现出了抗肿瘤活性。研究表明，ACBD6和ACSL1这两种蛋白在肉豆蔻酰辅酶A的运输与代谢过程中发挥着至关重要的作用，这一发现可能与某些癌症的发展机制密切相关。为了有效利用这一机制作为治疗靶点，有必要深入探究癌细胞如何调控脂质辅酶A的生物合成过程。此外，研究还指出，通过干预N-肉豆蔻酰化蛋白的分子伴侣，比如UNC119同源物，可以间接地调节N-肉豆蔻酰化过程。然而，针对UNC119的当前抑制剂在调控致癌信号传导方面的效果尚有限，这表明需要进一步研究和开发更有效的分子工具和药物策略。图片来源：123RF 与S-棕榈酰化相关的潜在靶点在人类中，S-棕榈酰化是一种由ZDHHC家族的23种蛋白所催化的可逆脂质修饰过程。棕榈酰基团的去除则由多种酰基蛋白硫酯酶（APT）催化，其中包括APT1、APT2及包含ABHD结构域的蛋白。虽然ZDHHC蛋白催化了大多数棕榈酰化事件，但它如何与APT蛋白相互作用以招募特定底物的机制目前还未完全阐明。目前已知超过2400种哺乳动物蛋白经历棕榈酰化，这些蛋白覆盖了广泛的功能类别，其中包括超过150种与癌症相关的致癌蛋白。转录增强相关结构域（TEAD）蛋白TEAD蛋白是通过Hippo信号通路调控细胞生长与增殖的关键因子，其棕榈酰化对于保持蛋白质稳定性、与YAP/TAZ蛋白的相互作用、以及转录活性至关重要。YAP/TAZ与TEAD的过度激活在多种实体肿瘤中被观察到，促进了开发能够结合TEAD棕榈酸口袋并破坏YAP/TAZ与TEAD之间相互作用的抑制剂。例如GNE-7883，这是一种TEAD棕榈酰化抑制剂，能强效抑制YAP/TAZ与所有TEAD家族成员的结合，并在非小细胞肺癌模型中逆转了对KRAS G12C抑制剂的耐药性。TEAD棕榈酰化抑制剂在针对间皮瘤的临床试验中展现了良好的耐受性和抗肿瘤活性。图片来源：123RFSTAT3作为一种促炎和促肿瘤的转录因子，其棕榈酰化和去棕榈酰化循环受到ZDHHC7、ZDHHC3和APT2的调控。棕榈酰化作用使STAT3定位至质膜，在此处被JAK2磷酸化，随后通过APT2催化的去棕榈酰化促使磷酸化的STAT3转移到细胞核内，激活目标基因的表达。ZDHHC7的敲除或通过小分子抑制剂抑制APT2及其相关的棕榈酰化作用能够抑制STAT3的激活，为STAT3依赖性癌症的治疗提供了新靶点。值得注意的是，不同组织中调控STAT3及其上游棕榈酰化信号蛋白的ZDHHC蛋白可能存在差异，这为实现组织特异性的调控提供了可能。ZDHHC在癌症免疫治疗中，蛋白棕榈酰化作用展现出了潜在的重要作用，尤其是在调节免疫检查点蛋白（如PD-L1和PD-1）的功能方面。这些蛋白的棕榈酰化过程主要由ZDHHC3和ZDHHC9酶催化，该过程可以阻止它们被泛素化和降解，从而影响免疫检查点的功能。不过，这一机制在T细胞环境中的效应还需进一步的实验验证。最近的一项研究通过在体内抑制ZDHHC20的活性，揭示了其在胰腺导管腺癌（PDAC）小鼠模型中促进转移性生长的关键作用。研究发现，ZDHHC20的活性仅与肿瘤的转移有关，而对细胞的存活能力或原发性肿瘤的生长并无显著影响。该机制可能涉及到通过棕榈酰化作用调节细胞表面受体，从而抑制肿瘤微环境中的先天免疫反应。值得注意的是，虽然ZDHHC20基因敲除的小鼠的存活和生育能力与正常小鼠无异，但在PDAC患者中观察到ZDHHC20的高表达水平与较差的生存预后相关联。因此，开发ZDHHC20抑制剂可能成为一种新的治疗策略。此外，干扰素（IFNs）在调节机体对抗肿瘤细胞的免疫反应中扮演着关键角色，其中IFNα作为癌症治疗的一部分已得到FDA的批准。在某些对免疫治疗产生耐药的患者中，观察到对IFNγ应答较弱，这一现象与IFNγ受体IFNGR1的加速降解有关。IFNGR1的棕榈酰化过程促进了其向溶酶体的运输和随后的降解。有研究表明，通过使用非特异性脂质生物合成抑制剂如丝裂霉素稳定IFNGR1，可以增强肿瘤的免疫反应，使肿瘤细胞对免疫治疗更加敏感。这些发现为癌症免疫治疗提供了新的潜在策略，突显了深入研究蛋白质棕榈酰化在肿瘤免疫调控中作用的重要性。与分泌性蛋白脂化相关的潜在靶点形态发生素蛋白Wnt和Hh在胚胎发育及成人干细胞生态位的维持中起关键作用。这些分泌性蛋白需通过膜结合O-乙酰转移酶（MBOATs）进行脂化修饰才能进行分泌或信号传导。具体而言，Wnt家族由PORCN酶在保守型丝氨酸位点进行脂化修饰，而Hh家族在去除内质网信号肽后由HHAT酶在N-末端进行棕榈酰化，并在C-末端进行自催化的胆固醇化。这些形态发生素蛋白与MBOAT酶的关系高度特异，为通过抑制PORCN或HHAT特异性地靶向Wnt或Hh信号传导提供了可能。Wnt和Hh信号通常协同作用以维持癌症干细胞的活性，这在结直肠癌、胰腺导管腺癌和基底细胞癌中扮演着显著的角色。PORCN酶PORCN抑制剂（PORCNi）已经进入临床试验十年之久，但由于长期使用可能导致的骨密度降低等副作用，以及疗效尚不明确，它们还未成为癌症治疗的常规手段。Wnt信号通路被认为能通过排除肿瘤微环境中的T细胞来促进免疫抑制。一些研究表明，PORCNi可能改变免疫特征，从而支持其与抗PD-1检查点抑制剂的联合使用，目前相关的1期和2期临床试验正在进行中。最近报道的PORCN酶及其与WNT974复合物的结构为设计更具选择性的PORCNi开辟了新途径。在Hh信号通路中，Hh配体的N-棕榈酰化对于其在细胞外的分布和与受体PTCH1的结合至关重要，这一过程进而影响下游SMO的激活以及通过GLI转录因子进行的促存活信号传导。目前，尚未发现Hh的N-棕榈酰基水解酶，因此，预计HHAT抑制剂只影响三种Hh配体与PTCH1的结合，HHAT抑制剂很可能比PORCNi更具选择性和针对性。HHAT酶2021年，研究人员通过冷冻电子显微镜首次解析了HHAT的三维结构，揭示了其十次跨膜折叠构象和活性位点的细节，为HHAT抑制剂的开发提供了重要的结构基础。这些研究成果强调了HHAT在特异性地催化Hh配体脂化修饰中的作用，而非参与其他脂质的运输过程。此外，最近开发的Acyl-cLIP技术，一种基于酰基偶联的亲脂性极化诱导的检测方法，为高通量筛选出更具选择性的HHAT抑制剂提供了可能，为临床抗癌靶点的验证提供了工具。图片来源：123RF结语蛋白质脂质化在癌症的发展中扮演了关键角色，近期研究的进展为开发新的治疗策略带来了前所未有的机遇。特别是，直接靶向蛋白质脂质化位点及其相互作用位点已成为研究的重点领域，其中新一代的蛋白质脂质化抑制剂在研究中展现出了显著的效力与选择性。值得一提的是，2020年11月，法尼基转移酶抑制剂lonafarnib（商品名：Zokinvy）获批用于治疗早老症，凸显了蛋白质脂化作为治疗靶点的可行性。深入了解蛋白质脂化失调在癌症中的作用，特别是通过开发新的分析手段以检测和量化蛋白质脂化修饰的变化，对于精准制定治疗方案至关重要。结合蛋白质脂化抑制剂与特定的靶向疗法，有望在可接受剂量下实现持久且稳定的治疗效果。▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Tate, E.W., Soday, L., de la Lastra, A.L. et al. Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets. Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00666-x免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

2022-11-22

·BioSpace

Pacylex Granted FDA Fast Track Designation for PCLX-001 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Edmonton, Alberta--(News - November 22, 2022) - Pacylex, a clinical-stage N-myristoyltransferase (NMT) inhibitor company developing first-in-class therapies for leukemia, lymphoma, and solid tumor cancers, today announced that the U.S. Food and Drug Administration (FDA) has granted PCLX-001 Fast Track Designation for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML). Fast Track is a process to facilitate drug development and expedite the review of new drugs and vaccines intended to treat or prevent serious conditions and address unmet medical needs. To view the full announcement, including downloadable images, bios, and more, click here. Key Takeaways: PCLX-001 is a first-in-class N-myristoyltransferase inhibitor which inhibits signaling necessary for cancer cell proliferation and survival in leukemia and lymphoma. PCLX-001 is currently in clinical studies at 4 hospitals in Canada in non-Hodgkin Lymphoma and solid tumor patients. The company also recently received FDA Orphan Drug Designation for PCLX-001 in AML and IND clearance for a Phase 1/2 study to start in the next quarter. Click image above to view full announcement. About Acute Myeloid Leukemia In 2020, more than 474,500 new cases of leukemia were reported globally with more than 311,500 deaths (Source: 1). In 2017, AML accounted for 23.1% of total leukemia cases worldwide, and it is one of the most common types of leukemia in adults (Source: 2,3). In the U.S., an estimated 20,050 new cases of AML will be diagnosed in 2022 with the five-year survival rate reported at 30.5% (Source: 2,4). The conventional treatment for newly diagnosed AML is intensive induction and consolidation chemotherapy with HSCT for eligible patients (Source: 5). The introduction of new targeted therapies in recent years has added to the standard of care and improved outcomes for some patients with molecularly defined AML subtypes (Source: 6). However, there remains a need to improve survival for the majority of patients with AML (Source: 5). PCLX-001 PCLX-001 (aka DDD86481) is a first-in-class, small molecule NMT inhibitor originally developed by the University of Dundee Drug Discovery Unit as part of a program to treat African sleeping sickness, funded by Welcome Trust. Pacylex is developing PCLX-001 in the form of a once-a-day pill initially to treat leukemia and lymphoma. PCLX-001 has also been shown to inhibit the growth of lung and breast cancer tumors in animal models. In leukemia, lymphoma and breast cancer patients, the levels of NMT2 are correlated with survival, suggesting an important biological role in these cancers. About Pacylex Pacylex is a pharmaceutical company headquartered in Edmonton, Alberta, Canada, targeting hematologic and solid cancers with a new first-in-class therapeutic, PCLX-001. Pacylex's technology combines new insights from Dr. Luc Berthiaume of the University of Alberta connecting myristoylation to cancer with a family of high quality myristoylation inhibitors Pacylex licensed from the University of Dundee. PCLX-001 is the lead drug in a new class of NMT inhibitors, enabling Pacylex to exploit NMTs as new clinical targets for cancer treatment. Pacylex initiated clinical studies in Canada in the fall of 2021 in non-Hodgkin lymphoma and solid tumors. Pacylex is also receiving support from an Alberta Innovates AICE grant in 2020, and the research leading to this breakthrough was supported in part by the Alberta Cancer Foundation and the Cure Cancer Foundation. The US Department of Defense is supporting the initial clinical investigation of PCLX-001 in AML patients. For more information: Pacylex Pharmaceuticals Contact: Michael J. Weickert CEO, Pacylex Pharmaceuticals, Inc. E: michael.weickert@pacylex.com P: 650-218-1840 Twitter @Pacylex ( ) LinkedIn ( ) Facebook ( ) Reportable page: ( ) #cancer, #lymphoma, #leukemia, #albertacancer, #Pacylex, #PCLX001, #UAlberta; #UAlberta_FoMD; #Worldslongestgame, #ASH22, #MDACC, #AML References 1 Global Cancer Observatory. Population Fact Sheet: World. Updated March 2021. 2 American Cancer Society: Key Statistics for Acute Myeloid Leukemia. Updated January 2022. 3 Dong Y et al. Exp Hematol Oncol. 2020;9:14. 4 National Cancer Institute SEER Program. Cancer Stat Facts: Acute Myeloid Leukemia 5 Daver et al. Blood Cancer J. 2020;10(10):107. 6 Short et al. Cancer Discov. 2020;10:506-25. Contacts: Michael Weickert Ph.D 650-218-1840 michael.weickert@pacylex.com Source: Pacylex To view the source version of this press release, please visit

快速通道孤儿药临床研究

2022-11-03

·BioSpace

Pacylex Will Present Phase 1 Clinical Experience with PCLX-001 and Rationale for Expanding into Acute Myeloid Leukemia Patients at ASH 2022

Edmonton, Alberta--(News - November 3, 2022) - Pacylex today announced that data from the ongoing Phase 1 dose escalation clinical trial of PCLX-001, an N-myristoyltransferase (NMT) inhibitor, as well as the scientific rationale for its use in acute myeloid leukemia (AML) patients, will be presented at the American Society of Hematology (ASH) Annual Meeting and Exposition from 10-13 December 2022. The ongoing study is in Non-Hodgkin's Lymphoma and solid tumor patients and the company will present the non-clinical evidence that AML patients may benefit as well. To view the full announcement, including downloadable images, bios, and more, click here. Key Takeaways: Pacylex non-clinical data which strongly supports expanding clinical investigations of PCLX-001 to acute myeloid leukemia (AML) will be presented at the American Society of Hematology Annual Meeting. PCLX-001 safety experience in 17 lymphoma and solid tumor patients provides confidence to proceeding with a second clinical indication in AML. The company received FDA Orphan Drug Designation for PCLX-001 in AML and clearance of an IND to start dosing AML patients. Click image above to view full announcement. PCLX-001 PCLX-001 (aka DDD86481) is a first-in-class, small molecule NMT inhibitor originally developed by the University of Dundee Drug Discovery Unit as part of a program to treat African sleeping sickness, funded by Welcome Trust. Pacylex is developing PCLX-001 in the form of a once-a-day pill initially to treat leukemia and lymphoma. PCLX-001 has also been shown to inhibit the growth of lung and breast cancer tumors in animal models. In leukemia, lymphoma and breast cancer patients, the levels of NMT2 is correlated with survival, suggesting an important biological role in these cancers. About Pacylex Pacylex is a pharmaceutical company headquartered in Edmonton, Alberta, Canada, targeting hematologic and solid cancers with a new first-in-class therapeutic, PCLX-001. Pacylex's technology combines new insights from Dr. Luc Berthiaume of the University of Alberta connecting myristoylation to cancer with a family of high quality myristoylation inhibitors Pacylex licensed from the University of Dundee. PCLX-001 is the lead drug in a new class of NMT inhibitors, enabling Pacylex to exploit NMTs as new clinical targets for cancer treatment. Pacylex initiated clinical studies in Canada in the fall of 2021 in non-Hodgkin lymphoma and solid tumors and will soon initiate clinical studies in the US in acute myeloid leukemia patients. Pacylex is also receiving support from an Alberta Innovates AICE grant in 2020, and the research leading to this breakthrough was supported in part by the Alberta Cancer Foundation and the Cure Cancer Foundation. The US Department of Defense is supporting the initial clinical investigation of PCLX-001 in AML patients. For more information: Pacylex Pharmaceuticals Contact: Michael J. Weickert CEO, Pacylex Pharmaceuticals, Inc. E: michael.weickert@pacylex.com P: 650-218-1840 Twitter @Pacylex ( ) LinkedIn ( ) Facebook ( ) Reportable page: ( ) #cancer, #lymphoma, #leukemia, #albertacancer, #Pacylex, #PCLX001, #UAlberta; #UAlberta_FoMD; #Worldslongestgame, #ASH22 Contacts: Michael Weickert Ph.D 650-218-1840 michael.weickert@pacylex.com Source: Pacylex To view the source version of this press release, please visit

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