NMT1

前言蛋白质脂质化是一类不同的翻译后修饰（PTM），由40多种酶调节，靶向3000多个位点的1000多种底物。脂质蛋白包括150多种癌蛋白，涉及癌症起始、进展和免疫的介质、受体激酶、转录因子、G蛋白偶联受体和细胞外信号蛋白。脂质化调节其蛋白质底物与细胞膜的物理相互作用，调节蛋白质信号传导和运输，并在代谢和免疫中发挥关键作用。蛋白质脂质化可大致分为两种类型：组成型脂质化，其中脂质作为蛋白质合成或成熟的组成部分附着；以及动态脂质化，例如在信号级联过程中，从成熟蛋白质中动态添加或去除脂质。对复杂和动态的蛋白质脂质化景观进行分析具有相当大的挑战，癌症中的脂质PTM及其失调为癌症药物发现提供了目前尚未开发的潜在靶点来源。因此，我们需要加强对癌症靶向蛋白脂质化途径的理解，推动靶向蛋白脂质化癌症药物的临床研究，提供靶向蛋白质脂质化的新型肿瘤疗法。癌症中的S-丙烯酰化S-丙烯酰化在蛋白质合成后迅速发生，并且是不可逆的，在蛋白质的一生中持续存在。这一过程是由四种蛋白质丙炔基转移酶，法尼基转移酶（FTase）和香叶基-香叶基转移酶I、II和III（GGTase I–III），在C末端或附近的半胱氨酸残基上添加类异戊二烯脂质引发的。最突出的丙酰化癌蛋白是四种RAS亚型（KRAS4A、KRAS4B、NRAS和HRAS），约占19%的突变癌症患者，尤其是那些对治疗最具耐药性的患者。有证据表明，在健康人和疾病患者中，异戊二烯化参与了这些癌蛋白的调节。RAS激活突变普遍保留了膜定位和致癌信号传导所需的CaaX盒预酰化位点，以及KRAS4A、NRAS和HRAS的二次棕榈酰化所需的位点。异丙基半胱氨酸羧甲基转移酶（ICMT）对丙酰化修饰的进一步处理影响RAS蛋白定位和RAS-驱动的恶性转化。最近的研究表明，ICMT还可能有助于癌症细胞增殖和存活、DNA损伤修复、干性和自我更新。通过靶向脂质化破坏RAS定位和下游信号传导已被广泛研究作为靶向RAS突变体的一种方法。2020年，FTase抑制剂（FTI） lonafarnib成为首个获批的抗蛋白质-脂质转移酶的药物，靶向罕见病早衰亚型中层粘连蛋白a法尼酰化的异常保留。此外，FTI  tipifarnib已被授予针对携带HRAS突变的HNSCC的突破性疗法。不幸的是，由于剂量限制、靶向血液毒性和耐药性，II期临床试验中最初表现出的高反应率很短暂。为了降低耐药性，目前正在研究联合疗法。此外，一种GGTase I抑制剂（GGTI-2418，也称为PTX-100）已进入T细胞淋巴瘤（NCT03900442）的Ib期临床试验。癌症中N-肉豆蔻酰化N-肉豆蔻酰化是一种不可逆的C14:0脂质PTM，由N-肉豆蔻基转移酶（NMT）催化，从肉豆蔻基CoA（Myr-CoA）转移到人类蛋白质组中200多种底物蛋白的N-末端甘氨酸。肉豆蔻酰化可以介导动态膜结合，触发次级PTM（如S-酰化）和蛋白质相互作用，调节蛋白质复合物的酶活性，或变构调节可溶性蛋白质。SRC家族激酶是NMT的首批鉴定底物之一，随后的研究表明，NMT通过多种致癌途径调节底物。例如，肉豆蔻酰化将脱铁抑制蛋白1（FSP1）靶向膜，在膜中它防止氧化脂质物质的积累。NMT底物包括传统方法无法治疗的致癌蛋白家族，包括ADP核糖基化因子蛋白（ARFs）、ARF样蛋白（ARLs）和高尔基体重组堆叠蛋白（GOASP），它们调节ER–高尔基体运输，参与线粒体复合体I组装等。asciminib是一种口服给药的小分子选择性变构抑制剂，靶向BCR-ABL1酪氨酸激酶的肉豆蔻酰口袋，由诺华制药研发，主要用于费城染色体阳性（Ph+）慢性粒细胞白血病（CML）。于2021年获得FDA批准，在激酶抑制剂耐药性癌症中显示出疗效，并在临床试验中显示出持久的反应（NCT02081378，NCT03106779）。NMT活性也可以直接靶向，为对抗多种其他不可治疗的癌蛋白提供了一个独特的干预点，这些癌蛋白汇聚在调节蛋白质合成的途径上。来自几项体外和体内研究的证据，包括膀胱癌和B细胞淋巴瘤的异种移植物模型，以及肺癌的同基因小鼠模型中，抑制NMT通过LAMTOR1的功能丧失诱导肿瘤细胞中的蛋白质合成阻断。最后，NMT抑制剂偶联的抗体偶联药物（ADC）显示出显著的提高疗效和耐受性的潜力，最近在乳腺癌、胃癌和前列腺癌的异种移植物模型中报道了肿瘤的完全消退。这些数据表明，NMT抑制剂的靶向递送可能扩大靶向癌症范围。癌症中的S-棕榈酰化在人类中，S-棕榈酰化由ZDHHC家族中的23种蛋白质催化，其去除可由丝氨酸水解酶超家族的多种APT催化，包括APT1、APT2和含有α/β水解酶结构域（ABHD）的蛋白质ABHD17A、ABHD17B、ABHD17 C和ABHD10，使S-棕榈酰化成为一类独特的可逆和动态的蛋白质脂质化。在超过100项蛋白质组学和生物化学研究中，超过2400种哺乳动物蛋白质发生棕榈酰化。这些蛋白质包括整合膜蛋白、外周膜蛋白、细胞质信号蛋白和转录因子。包括NRAS、KRAS4A、HRAS、EGFR和p53在内的癌蛋白依赖于S-棕榈酰化循环来调节其定位、活性或相互作用因子，已知大于150种癌蛋白是S-棕榈酰酸化的。棕榈酰化是致癌激酶的重要调节因子，包括肝细胞生长因子受体酪氨酸激酶MET，其中ER中的棕榈酰化对运输、稳定性和表达是很重要的。此外，有证据表明，EGFR信号传导对其棕榈酰化有促进和抑制作用，这可能是由于存在多个棕榈酰化位点，这些位点由不同的ZDHHC蛋白调节，并具有不同的功能效应。棕榈酰化还调节G蛋白偶联受体的活性，包括黑素皮质素-1受体（MC1R）的活性，后者在紫外线照射后驱动黑色素的产生和DNA修复。因此，棕榈酰化受损的MC1R会增加黑色素瘤的风险。S-棕榈酰化与癌症治疗的耐药性也有关。例如，ZDHHC2介导的线粒体酰甘油激酶（AGK）的棕榈酰化通过激活AKT–mTOR信号增加肾细胞癌中舒尼替尼的耐药性，而ZDHHC16介导的PCSK9的棕榈酰基化通过激活PI3K–AKT途径诱导癌症中索拉非尼的耐药性。转录增强相关结构域（TEAD）蛋白在Hippo信号传导下游调节细胞生长和增殖。GNE-7883是最近报道的一种优化的TEAD棕榈酰化抑制剂，它强烈抑制YAP/TAZ与所有四个TEAD家族成员（TEAD1–4）的结合，并在NSCLC的患者衍生异种移植物模型中逆转Hippo驱动的对KRAS-G12C抑制剂的内在和获得性耐药。第一批进入间皮瘤I期临床试验的TEAD自棕榈酰化抑制剂显示出良好的耐受性和抗肿瘤活性（NCT05228015和NCT04665206）。小结调节蛋白质脂质化为我们提供一种独特的方法，通过控制其膜结合、运输、蛋白质稳定性和蛋白质-蛋白质相互作用，靶向其他难以治疗的癌蛋白。随着我们对癌症中蛋白质脂质化相关性认识的发展，新的治疗机会可能会出现。参考文献：1.Proteinlipidation in cancer: mechanisms, dysregulation and emerging drug targets. NatRev Cancer.2024 Feb 29免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

▎药明康德内容团队编辑本期看点1. 一项1b期研究数据显示，基于CD73抑制剂quemliclustat的联合治疗方案在未经治疗的转移性胰腺癌患者中具有治疗潜力，患者的总生存期（OS）较单独化疗的历史基准数据延长5.9个月。2. Panbela Therapeutics公司基于CPP-1X（DFMO）的联合疗法在神经母细胞瘤患者中展现积极疗效，3名完成治疗的患者在没有接受额外治疗的情况下，已保持4年多没有出现疾病进展。3. Fostrox联用激酶抑制剂lenvatinib治疗晚期肝细胞癌（HCC）展现积极结果，18周时的疾病控制率（DCR）超过60%。药明康德内容团队整理Quemliclustat：公布1b期临床试验数据 Arcus Biosciences公司与吉利德科学（Gilead Sciences）公司公布了其共同开展的1b期研究ARC-8的OS数据。ARC-8是一项针对既往未经治疗的转移性胰腺导管腺癌（mPDAC）患者的研究，旨在评估一种在研小分子CD73抑制剂quemliclustat（下表中简称“Q”）＋化疗（下表中简称“G/nP”）±一种在研抗PD-1抗体zimberelimab（下表中简称“Z”）的疗效。▲ARC-8研究的疗效数据（图片来源：参考资料[2]）截止2023年6月19日的数据，以quemliclustat为基础的两种治疗方案的中位OS为15.7个月，单独化疗组的历史基准数据为9.8个月。相比于单独化疗组，接受以quemliclustat为基础的两种治疗方案的患者的死亡风险降低了37%（HR=0.63；95% CI：0.47-0.85，p=0.0030）。安全性方面，未发现新的安全性信号。最常见的不良事件（≥3级）是中性粒细胞减少和贫血。CPP-1X（DFMO）：公布1期临床试验数据Panbela Therapeutics公司公布了CPP-1X（DFMO）治疗神经母细胞瘤的临床研究数据。这项发表在British Journal of Cancer上的研究旨在评估大剂量CPP-1X与塞来昔布（celecoxib）联用标准化疗治疗接受过大量先前治疗的神经母细胞瘤患者的耐受性和活性。结果显示，CPP-1X的耐受性良好，患者的中位进展时间（time-to-progression）为19.8个月。最佳总缓解包括2例部分缓解（PR）、4例轻微缓解（MR）、10例疾病稳定（SD）、7例疾病进展（PD）和1例无法评估的患者，无完全缓解（CR）患者。所有总缓解为PR或MR的患者都保持了这种缓解，直到停止或完成治疗。客观缓解率（CR+PR）为9%，任意缓解率（CR+PR+MR）为26%。2年后，该队列的无进展生存率为29.5%。值得注意的是，有3位患者完成了治疗，并且在治疗结束后的四年多时间里，在没有额外治疗的情况下，仍未出现疾病进展。Fostroxacitabine bralpamide（fostrox）：公布1b/2a期临床试验的新数据Medivir公司公布了其正在进行的1b/2a期研究的积极新数据。该研究旨在评估fostrox联用激酶抑制剂Lenvima（lenvatinib）治疗目前一线或二线治疗无效或不能耐受的晚期HCC患者的安全性和疗效。Fostrox是一种核苷酸DNA聚合酶抑制剂口服前药，以肝脏为靶器官，旨在选择性将药物递送到肝细胞中治疗HCC，并将副作用降至最低。该研究目前仍在进行中，约有超过40%的患者仍在接受治疗，仅有5%的人因不良反应而停用fostrox，需要减少剂量的人数也低于预期。该联合疗法的耐受性良好，没有新的、意外的安全事件。此次公布的结果显示，大多数患者都能持续获得临床治疗效果，治疗18周时的DCR高达61%，总缓解率（ORR）为25%，中位进展时间为5.1个月。截至目前，持续缓解时间最长的患者在接受治疗约17个月后仍保持着PR。PMB-CT01：公布1期临床试验中首位患者的数据PeproMene Bio公司公布了其候选CAR-T细胞疗法PMB-CT01治疗复发/难治性急性B淋巴细胞白血病（B-ALL）患者的1期临床试验中首位患者的数据。PMB-CT01是一种潜在“first-in-class”的B细胞活化因子受体（BAFFR）靶向自体CAR-T细胞疗法。BAFFR是肿瘤坏死因子（TNF）受体超家族成员，是BAFF的主要受体，几乎只在B细胞上表达。由于BAFFR信号能促进正常B细胞的增殖，而且似乎是B细胞存活所必需的，因此肿瘤细胞不太可能通过丢失BAFFR抗原来逃避免疫反应。这种独特的特性使BAFFR靶向的CAR-T细胞疗法具有治疗B细胞恶性肿瘤的巨大潜力。BAFFR靶向的CAR-T细胞疗法是使用抗BAFFR scFv（单链可变区）抗体与包含CD3ζ和4-1BB的第2代信号转导结构域构建的。研究发现，BAFFR靶向的CAR-T细胞能在体外和动物模型中杀死人类淋巴瘤和白血病细胞。PeproMene Bio公司已从希望之城（City of Hope）获得与PMB-CT01相关的知识产权许可。此次公布的数据显示，首例患者对PMB-CT01的耐受性良好，只出现了轻微的在预期内的毒性反应，并在接受治疗一个月后达到了CR。AB126：IND申请获得FDA许可Aruna Bio公司宣布美国FDA已批准了其主导项目AB126的IND申请。该公司预计将于2024年上半年启动AB126治疗急性缺血性中风患者的1b/2a期临床试验。AB126是一种未经修饰的神经源性外泌体，天然具有穿越血脑屏障的能力。有证据表明，AB126具有抗炎和神经保护特性。新闻稿指出，AB126是首款进入人体试验阶段的针对神经系统适应症的外泌体疗法。KVA12123：公布1/2期临床试验的新数据Kineta公司公布了其正在进行的1/2期临床试验的最新进展，该试验评估了其新型在研VISTA阻断免疫疗法KVA12123在晚期实体瘤患者中的治疗效果。KVA12123是一种单克隆抗体疗法，需每周输注两次。通过将独特的表位结合与优化的IgG1 Fc区相结合，KVA12123单药在临床前模型中显示出强大的肿瘤生长抑制作用，且在临床试验中没有报告细胞因子释放综合征（CRS）。KVA12123已被证明能降低VISTA靶点的风险，并提供了一种新的方法来解决肿瘤微环境中的免疫抑制问题，其作用机制与以T细胞为重点的疗法不同且互补。此次公布的结果显示，KVA12123的耐受性良好，单药或与帕博利珠单抗联用在任何剂量水平上都未出现剂量限制性毒性或细胞因子相关不良事件。此外，KVA12123单药可与给药剂量成比例地诱导强抗肿瘤活性所需的促炎生物标志物，显示了阻断VISTA的靶向作用。Onvansertib：公布1b期临床试验数据Cardiff Oncology公司公布了其polo样激酶1（PLK1）抑制剂onvansertib二线治疗携带KRAS突变的转移性结直肠癌（mCRC）患者的1b/2期研究结果。Onvansertib是一种潜在“first-in-class”的第三代口服高选择性丝氨酸/苏氨酸PLK1抑制剂，在各种实体瘤中作为单药或与多种化疗药物联合使用均显示出良好的耐受性。此次公布的结果显示，onvansertib+标准疗法（SoC）化疗+贝伐珠单抗的组合疗法的安全性可控，疗效良好。在44%的患者中观察到PR，中位缓解持续时间为9.5个月。早期的循环肿瘤DNA（ctDNA）动力学可以预测治疗效果。这些积极数据促使Cardiff Oncology公司决定启动onvansertib一线治疗携带RAS突变的mCRC患者的临床试验。Zelenirstat（PCLX-001）：公布1期临床试验数据Pacylex Pharmaceuticals公司公布了其N-肉豆蔻酰转移酶（NMT）抑制剂zelenirstat治疗复发/难治性结直肠癌和其他癌症的1期剂量递增的安全性和耐受性研究结果。Zelenirstat是一种潜在“first-in-class”的口服小分子NMT抑制剂，目前正在开发用于治疗白血病、淋巴瘤和实体瘤。在动物模型中，zelenirstat能在体外选择性地杀死癌细胞，并能使血液恶性肿瘤消退，抑制肺癌和乳腺癌的生长。在急性髓细胞性白血病模型中，zelenirstat能杀死白血病干细胞群，并使正常骨髓细胞再生和生长。此次公布的结果显示，在推荐的2期剂量下，zelenirstat延长了胃肠道和其他癌症患者的无进展生存期。其中，一位此前曾接受过7线治疗后复发的晚期结直肠癌患者在接受了zelenirstat治疗后，癌胚抗原（CEA）和肿瘤体积减少了约50%。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲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（可上下滑动查看）[1] Aruna Bio Announces FDA Clearance of IND for Lead Program AB126, Enabling the First Exosome to Enter in Human Clinical Trials for a Neurological Indication. Retrieved January 19, 2024, from https://www.globenewswire.com/news-release/2024/01/16/2809846/0/en/Aruna-Bio-Announces-FDA-Clearance-of-IND-for-Lead-Program-AB126-Enabling-the-First-Exosome-to-Enter-in-Human-Clinical-Trials-for-a-Neurological-Indication.html[2] Data from a Phase 1b Study of Quemliclustat-Based Regimens Showed Promising Overall Survival in Treatment-Naïve Metastatic Pancreatic Cancer. Retrieved January 19, 2024, from https://www.businesswire.com/news/home/20240116940666/en[3] Kairos Pharma Doses First Patients in Phase 1 Trial of Lead Drug Candidate ENV105 with Osimertinib to Improve Therapy Sensitivity for EGFR-Driven Lung Cancer. Retrieved January 19, 2024, from https://www.globenewswire.com/news-release/2024/01/16/2810031/0/en/Kairos-Pharma-Doses-First-Patients-in-Phase-1-Trial-of-Lead-Drug-Candidate-ENV105-with-Osimertinib-to-Improve-Therapy-Sensitivity-for-EGFR-Driven-Lung-Cancer.html[4] FDA CLEARANCE OF AMPLIA'S IND FOR PANCREATIC CANCER TRIAL IN US. Retrieved January 19, 2024, from https://www.prnewswire.com/news-releases/fda-clearance-of-amplias-ind-for-pancreatic-cancer-trial-in-us-302037692.html[5] PeproMene Bio 宣布在 PMB-CT01 1 期临床试验中，B-ALL 患者病情得到完全缓解 | 取得成功. Retrieved January 19, 2024, from https://www.prnasia.com/story/434368-1.shtml[6] Oxford BioTherapeutics Announces First Patient Dosed with OBT076 in Phase 1b Trial in Adenoid Cystic Carcinomas of the Head and Neck. Retrieved January 19, 2024, from https://www.globenewswire.com/news-release/2024/01/18/2811280/0/en/Oxford-BioTherapeutics-Announces-First-Patient-Dosed-with-OBT076-in-Phase-1b-Trial-in-Adenoid-Cystic-Carcinomas-of-the-Head-and-Neck.html[7] Cardiff Oncology Announces Publication of Data from Phase 1b study in second-line KRAS-mutated mCRC in Clinical Cancer Research. Retrieved January 19, 2024, from https://www.prnewswire.com/news-releases/cardiff-oncology-announces-publication-of-data-from-phase-1b-study-in-second-line-kras-mutated-mcrc-in-clinical-cancer-research-302036963.html[8] Sensorion Announces Approval to Initiate Lead Gene Therapy Candidate SENS-501 (OTOF-GT) into a Phase 1/2 Clinical Trial in some European Countries. Retrieved January 19, 2024, from https://www.businesswire.com/news/home/20240118230763/en[9] Vor Bio Doses First AML Patient with VCAR33 (ALLO) and Provides Corporate Update. Retrieved January 19, 2024, from https://ir.vorbio.com/news-releases/news-release-details/vor-bio-doses-first-aml-patient-vcar33-allo-and-provides[10] Panbela Announces Publication of Clinical Data Titled: Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: A New Approaches to Neuroblastoma Therapy Trial. Retrieved January 19, 2024, from https://www.globenewswire.com/news-release/2024/01/18/2811519/37414/en/Panbela-Announces-Publication-of-Clinical-Data-Titled-Phase-1-study-of-high-dose-DFMO-celecoxib-cyclophosphamide-and-topotecan-for-patients-with-relapsed-neuroblastoma-A-New-Approa.html[11] Kineta Provides Update on its Ongoing Phase 1/2 VISTA-101 Clinical Trial of KVA12123 in Patients with Advanced Solid Tumors. Retrieved January 19, 2024, from https://kinetabio.com/2024/01/17/kineta-provides-update-on-its-ongoing-phase-1-2-vista-101-clinical-trial-of-kva12123-in-patients-with-advanced-solid-tumors/[12] Enlivex Receives IMOH Regulatory Authorization for the Initiation of a Multi-Country, Randomized, Controlled Phase I/II Trial Evaluating Allocetra in Up To 160 Patients with Moderate to Severe Knee Osteoarthritis. Retrieved January 19, 2024, from https://www.globenewswire.com/news-release/2024/01/17/2810641/0/en/Enlivex-Receives-IMOH-Regulatory-Authorization-for-the-Initiation-of-a-Multi-Country-Randomized-Controlled-Phase-I-II-Trial-Evaluating-Allocetra-in-Up-To-160-Patients-with-Moderate.html[13] Biomica Successfully Completes Phase I Trial Enrollment for Microbiome-Based Immuno-Oncology Drug. Retrieved January 19, 2024, from https://www.prnewswire.com/news-releases/biomica-successfully-completes-phase-i-trial-enrollment-for-microbiome-based-immuno-oncology-drug-302036967.html[14] Evommune Announces Initiation of a Phase 1 Trial of its MRGPRX2 Antagonist for the Treatment of Chronic Spontaneous Urticaria. Retrieved January 19, 2024, from https://www.prnewswire.com/news-releases/evommune-announces-initiation-of-a-phase-1-trial-of-its-mrgprx2-antagonist-for-the-treatment-of-chronic-spontaneous-urticaria-302037378.html[15] Inflammasome Therapeutics Announces First Patient Dosed in Phase I Diabetic Macular Edema Study of the Dual Inflammasome Inhibitor K8. Retrieved January 19, 2024, from https://www.businesswire.com/news/home/20240118557124/en[16] Fostrox + Lenvima shows further improved response rates and time to progression in advanced liver cancer (HCC) at ASCO GI Symposium. Retrieved January 19, 2024, from https://www.prnewswire.com/news-releases/fostrox--lenvima-shows-further-improved-response-rates-and-time-to-progression-in-advanced-liver-cancer-hcc-at-asco-gi-symposium-302036736.html[17] Pacylex Pharmaceuticals Reports Phase 1 Safety and Efficacy Results for Zelenirstat in Colorectal and other Cancers. Retrieved January 19, 2024, from https://www.newsfilecorp.com/release/194619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

Edmonton, Alberta--(News - January 17, 2024) - Pacylex Pharmaceuticals Inc. (Pacylex) is a clinical-stage pharmaceutical company focused on the development of a new class of targeted therapies, N-myristoyltransferase inhibitors (NMTi) for the treatment of hematologic and solid tumor cancers. Today Pacylex announced that the results of its Phase 1 dose escalation safety and tolerability study for zelenirstat, an investigational NMT inhibitor and Pacylex's lead product candidate, in refractory/ relapsed colorectal and other cancers, will be presented January 20, 2024, at the upcoming ASCO Gastrointestinal Cancers Symposium. To view the full announcement, including downloadable images, bios, and more, click here. Key Takeaways: Pacylex presents zelenirstat results in gastrointestinal and other cancer patients at the ASCO Gastrointestinal Cancers Symposium on January 18-20, 2024, in San Francisco, CA. Zelenirstat prolonged progression free survival in gastrointestinal and other cancer patients in Phase 1 at the recommended Phase 2 dose. An advanced colorectal cancer patient relapsed from 7 prior lines of therapy, has seen reductions of approximately 50% in CEA and tumor volumes so far with zelenirstat. Click image above to view full announcement. About zelenirstat (PCLX-001) Zelenirstat (formerly identified as PCLX-001) is a first-in-class, oral, small molecule N-myristoyltransferase (NMT) inhibitor being developed to treat patients with leukemia, lymphoma, and solid tumors. In animal models, zelenirstat selectively killed cancer cells in vitro and has been shown to regress hematologic malignancies and inhibit the growth of lung and breast cancer tumors. In AML models, zelenirstat killed leukemic stem enriched cell populations and allowed the regeneration and growth of normal bone marrow cells. About zelenirstat Phase 1 and 2 studies Pacylex completed the dose escalation phase of a Phase 1 multiple ascending dose safety, tolerability, and pharmacokinetics study on zelenirstat in R/R lymphoma and solid tumor patients (NCT04836195). A recommended Phase 2 dose was determined. Zelenirstat demonstrated an acceptable safety and tolerability profile, pharmacokinetics consistent with once daily oral dosing, and early signs of potential efficacy. Zelenirstat is currently being studied in a Phase 2a open-label study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of zelenirstat in patients with R/R B-cell non-Hodgkin Lymphoma (NHL). A separate Phase 2a cohort is planned in advanced solid malignancies who have progressed on all available standard therapies. About Pacylex Pharmaceuticals Pacylex is a clinical-stage pharmaceutical company headquartered in Edmonton, Alberta, Canada, targeting hematologic and solid cancers with orally bioavailable NMT inhibitors. Zelenirstat is the lead drug in a new class of NMT inhibitors, enabling Pacylex to exploit NMTs as new clinical targets for cancer treatment. Pacylex is conducting a multi-center Phase 1/2a study in Canada in patients with R/R NHL and advanced solid tumors. The IND for a Phase 1 multiple ascending dose study in acute myeloid leukemia (AML) has been cleared and the FDA has granted zelenirstat both Orphan Drug Designation and Fast Track Designation for AML. The US Department of Defense is supporting the initial clinical investigation of zelenirstat in patients with AML. The Cure Cancer Foundation supported initial clinical studies through its World's Longest Games. Forward-Looking Statements This press release contains forward-looking statements and forward-looking information within the meaning of applicable securities laws, such as statements relating to future events or the Company's future financial and operating performance, as well as the Company's business plans, growth initiatives, and objectives and prospects. Generally, forward-looking statements and forward-looking information may be identified by the use of forward-looking terminology, including the words "believe," "may," "will," "estimate," "continue," "anticipate," "intend," "should," "plan," "goal," "expect," "strategy," "future," "likely," "proposed," "scheduled," "forecast," "budget," "could," "would," variations of such words of phrases and other similar expressions, or by the use of words or phrases which state that certain actions, events or results may, could, would, or might occur or be achieved. However, the absence of these words does not mean that a statement is not forward looking. Forward-looking statements and forward-looking information are subject to numerous factors, risks and uncertainties that could cause actual results to differ materially, including, but not limited to, the Company's ability to successfully execute on its business plans and strategies, avoid delays in planned clinical trials, hire and retain key personnel, obtain appropriate or necessary governmental approvals to market potential products and obtain future funding for product development and working capital on commercially reasonable terms, changes in laws, and general macroeconomic conditions, including economic slowdowns, recessionary risks, rising inflation and interest rates, and supply chain disruptions. Forward-looking statements and forward-looking information are based on the beliefs of management as well as assumptions made by and information currently available to management as of the date hereof, and none of the Company or its affiliates undertakes any obligation to update or issue revisions to any forward-looking statements or forward-looking information contained herein to reflect any future events or circumstances, except as required by law. The foregoing does not constitute an offer or solicitation to acquire any securities in the Company or any related or associated entity or affiliate. The information contained herein is not intended as legal, tax, financial or investment advice. Furthermore, the information contained herein may not be applicable to or suitable for an individual's specific circumstances or needs. 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