IRF4

J Hematol Oncol.(一) 类花生酸(Eicosanoid)信号通路：二十烷基硫酸酯信号通路在生理过程和病理过程中都起着关键作用，通过类花生酸将炎症与癌症联系起来。二十碳多不饱和脂肪酸(PUFAs)是由20碳多不饱和脂肪酸(PUFAs)氧化而成的具有高度生物活性的衍生物，可通过环氧合酶(COX)、脂氧合酶(LOX)和细胞色素P450途径产生。COX途径产生前列腺素(PGs)和血栓素A(TXs)，而LOX途径则产生白三烯(LTs)和脂氧素(LXs)。COX信号通路COX家族中，COX-2的表达会受到早期炎症(proinflammatory)的上调，并被发现和调控多种肿瘤的进展相关。在炎症反应的早期阶段，COX-2衍生的PG被认为具有促炎功能。前列腺素D2、前列腺素E2、前列腺素F2α、前列腺素I2和血栓素A2是通过COX通路衍生的五种关键 PG。COX/PEG2COX-2/CSK3β信号还和上皮-间充质转化有关，通过抑制GSK3β来促进E-钙粘蛋白、β-连环蛋白和p120连环蛋白的蛋白质稳定性。抑制COX-2可以下调E-钙黏蛋白导致细胞死亡。PGE2通过其两种E-前列腺素受体EP2和EP4提供信号传导来塑造DC功能。EP4调节CD80、CD86、CD83、MHC II等激活标志物上调以及IL-10和IL-23的产生，引导cDC2成熟，促进T细胞扩增，形成抑制性而非促炎性T细胞群富集。PGE2还可能通过E2调节NK细胞合成IFN-γ来诱导免疫抑制，从而促进肿瘤的发生。肿瘤来源的前列腺素E2(PGE2)介导MDSC分化和获得促肿瘤特征。在PGE2暴露期间，EP2/4联合阻断M-MDSCs可防止这些抑制特征的发生。双重 EP2/EP4 PGE2受体拮抗剂增加了肿瘤微环境淋巴细胞浸润，并显着降低了多种肿瘤模型中的疾病负担。前列腺素D2则是COX-2的另一种代谢物，可能在慢性炎症和癌症中发挥双重作用。PGD2与其受体PTGDR2之间的相互作用抑制了胃癌细胞的自我更新，并减弱了胃癌的生长和转移。脂氧合酶(LOX)信号通路LOX通路负责将花生四烯酸代谢为白三烯，包括白三烯A4(LTA4)、LTB4和LTD4等。炎症细胞(包括白细胞、巨噬细胞和肥大细胞)是白三烯的主要来源。抑制LTB4受体可抑制炎症相关肿瘤的进展，LTD4则在肝细胞癌和慢性乙型肝炎患者的循环中上调。LOX途径主要包括5-LOX、12-LOX和15-LOX。5-LOX在上皮性癌和淋巴瘤中高度表达，具有促血管生成和促肿瘤活性。12-LOX通过激活整合素连接的激酶/NF-κB途径来促进肿瘤的生长。而15-LOX的代谢产物被发现能增强肿瘤相关炎症，既有促肿瘤作用又有抗肿瘤作用。另一种由LOX衍生的类花生酸脂毒素(lipoxins， LXs)则具有抗肿瘤作用。在前列腺癌中，LXA4通过抑制METTL3和或FPR2/IRF4途径，以促进巨噬细胞M2样极化。LXA4对炎性巨噬细胞极化的抑制作用与p-NF-κB p65和IRF5活性的下调有关，从而降低了LPS诱导的M1巨噬细胞通过FPR2/IRF5信号通路的表型和功能极化。 J Hematol Oncol.(二)JAK/STAT信号通路STAT3在炎症反应和肿瘤进展中发挥着广泛的作用。多种生长因子和细胞因子参与典型的STAT3通路，调节细胞分化、血管生成和肿瘤形成。IL-6和STAT3是启动肿瘤的肠上皮细胞生存和增殖所必需的。此外，在设计肠道的肿瘤如前列腺癌中，肠道生物失调增加了肠道通透性，肿瘤内的内毒素通过NF-κB/IL 6/STAT3轴促进了肿瘤的进展。Int Immunopharmacol.影响JAK/STAT通路的药物种类复杂，包括植物化学物质、合成药物和生物分子等等。Int Immunopharmacol.(三)金属代谢铁和ROS氧化还原铁代谢失调是肿瘤细胞的一个重要标志，在肿瘤细胞中，恶性肿瘤细胞需要大量的铁来生存和增殖。细胞色素P450酶、一氧化氮合酶、NADPH氧化酶和脂氧合酶等铁依赖性酶参与ROS的产生。同时，谷胱甘肽过氧化物酶GPX4是一种铁死亡的中枢抑制剂，GPX4利用还原性谷胱甘肽将活性的PUFA-PL-OOH还原为非活性和非致死性的PUFA-PL-OH。抑制Gpx4可通过诱导铁性死亡而增强治疗的抗肿瘤效应。十年铁死亡：双向调控与药物开发锌和NF-κB通路锌与许多炎症性细胞因子的产生和信号传递有关。当对应激刺激做出急性反应时，血浆锌浓度迅速下降。人体的锌代谢与ZIP8等锌转运蛋白的活性密切相关。在感染过程中，激活的NF-κB增加ZIP8的表达，ZIP8定位于细胞膜并调节锌的摄取。锌抑制了IKKβ的活性，从而减弱了炎症反应。参考文献：1.Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol. 2024 Mar 22;17(1):13. doi: 10.1186/s13045-024-01528-7.2.Balamurugan K,et al.Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight. 2023 Mar 22;8(6):e156057. doi: 10.1172/jci.insight.156057.3.Cuenca-Escalona J,et al.PGE2-EP4 signaling steers cDC2 maturation toward the induction of suppressive T-cell responses. Eur J Immunol. 2024 Mar;54(3):e2350770. doi: 10.1002/eji.202350770.4.Francica BJ,et al.Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors. Cancer Res Commun. 2023 Aug 8;3(8):1486-1500. doi: 10.1158/2767-9764.CRC-23-0249.5.Yuan J, et al. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway. Inflammopharmacology. 2022 Apr;30(2):487-498. doi: 10.1007/s10787-022-00942-y.6.Wang Y,et al. Deciphering JAK/STAT signaling pathway: A multifaceted approach to tumorigenesis, progression and therapeutic interventions. Int Immunopharmacol. 2024 Mar 22;131:111846. doi: 10.1016/j.intimp.2024.111846.·····

04月02日的《热心肠日报》，我们解读了 15 篇文献，关注：关节炎，FMT，IBD，流行病学，乳糜泻，致病菌，肠道免疫细胞，昆虫，LISCure，Affibody，瀚科迈博，加科思，飞鹤。 ​​ 该篇日报由R·AI辅助创作生成，人工审核校对。 肠上皮细胞坏死是肠道和关节炎发展之间的关键联系 Annals of the Rheumatic Diseases——[27.4] ① 这项研究确定了肠上皮细胞（IEC）坏死是肠道和关节炎发展之间的关键联系；② 关节炎发作时，IEC经历凋亡和坏死，导致肠道屏障功能受损；③ 在关节炎发作期间，HIF1α被确定为IEC中上调基因之一，在IEC中删除Hif1a增强了IEC坏死，引发肠道炎症并加重了关节炎；④ HIF1α是坏死诱导因子RIPK3的关键转录抑制因子，且在新发病风湿性关节炎患者的肠上皮中也发现了增强的RIPK3表达，表明肠上皮细胞发生坏死；⑤ 通过治疗性稳定HIF1α以及基于小分子的RIPK3抑制剂，在体外和体内拯救了肠道坏死，并抑制了关节炎的发展。 【原文信息】 Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery 2024-03-19 , doi: 10.1136/ard-2023-224491 Nature子刊：粪菌移植治疗溃疡性结肠炎的临床反应与GBP5有关 Nature Communications——[16.6] ① 分析粪菌移植（FMT）在溃疡性结肠炎（UC）患者身上的分子反应，探索FMT如何影响人类结肠黏膜的基因表达；② 相较于安慰剂干预，FMT改变了患者结肠黏膜转录组（受影响的基因数量：3 vs 75），包括对结构、代谢和炎症通路的调节；③ 在疾病缓解的患者中，调节的途径包括紧密连接、钙信号和异物代谢；④ GBP5和IRF4的下调与疾病缓解相关，而GBP5基因缺失的雌性小鼠比野生型同胞更能抵抗结肠炎，表现出更高的结肠IRF4磷酸化水平；⑤ 本研究表明GBP5可能在结肠炎的发展中起到负面作用，而FMT后的结肠粘膜反应能够区分UC患者是否实现缓解。 【原文信息】 Profiling the colonic mucosal response to fecal microbiota transplantation identifies a role for GBP5 in colitis in humans and mice 2024-03-26 , doi: 10.1038/s41467-024-46983-5 过去20年IBD的演变与变化 EClinicalMedicine——[15.1] ① 这项跨国多中心研究揭示了过去二十年间炎症性肠病（IBD）表现模式的变化，为改善患者的诊断、管理和预后提供了重要见解；② 共纳入6个国家1430名IBD患者（84.5%溃疡性结肠炎和14.3%克罗恩病），根据首次诊断时间分为3组：超过15年（A组）、5-15年（B组）和近5年（C组）；③ 与C组相比，A组和B组的肠外症状更为普遍、食物敏感率更高；④ 在C组中，左侧结肠炎成为溃疡性结肠炎最常见的亚型，且腹痛和腹胀的发生率增加，而腹泻的频率有所下降；⑤ 在C组中，克罗恩病患者上消化道症状更为普遍，无病发作的患者相对比例增加，表明IBD的管理和治疗可能有所改善。 【原文信息】 Inflammatory bowel disease evolution in the past two decades: a chronological multinational study 2024-03-15 , doi: 10.1016/j.eclinm.2024.102542 华北理工：IBD不会独立增加癌症风险 BMC Medicine——[9.3] ① 华北理工大学王友信团队探究了炎症性肠病（IBD）与癌症风险之间的关联，未发现两者之间因果关系的可靠遗传学证据，暴露于IBD可能并不独立地增加癌症风险；② 在东亚或欧洲人群中，IBD、克罗恩病（CD）或溃疡性结肠炎（UC）与癌症之间没有显著的遗传相关性；③ 东亚人群中未观察到IBD与癌症之间的显著因果关系，欧洲人群中CD与卵巢癌之间以及UC与非黑色素瘤皮肤癌之间存在显著关联；④ 多变量孟德尔随机化分析未发现以上任何显著关联；⑤ 使用共定位分析，在东亚或欧洲人群中，没有共享的因果变异体可以证明IBD、CD或UC与癌症之间的关联。 【原文信息】 Association between inflammatory bowel disease and cancer risk: evidence triangulation from genetic correlation, Mendelian randomization, and colocalization analyses across East Asian and European populations 2024-03-25 , doi: 10.1186/s12916-024-03352-9 麦醇溶蛋白肽寡聚化或可增加肠道通透性 Angewandte Chemie International Edition——[16.6] ① 本研究揭示了33-mer去酰胺化麦醇溶蛋白肽（DGP）在乳糜泻中的新作用机制；② 33-mer DGP是一种代谢修饰的小麦麸质抗原，可自发地组装成直径为24纳米的寡聚体；③ 33-mer DGP寡聚体主要呈现两种次级结构：主要的多脯氨酸II螺旋和次要的β-折叠结构；④ 33-mer DGP刺激下会导致肠上皮细胞模型Caco-2的通透性显著增加，伴随着紧密连接蛋白zonula occludens-1（ZO-1）的重新分布；⑤ 本研究为33-mer DGP对乳糜泻的影响进行了深入探究，并提示麦醇溶蛋白肽寡聚化与乳糜泻的相关性。 【原文信息】 The Celiac-Disease Superantigen Oligomerizes and Increases Permeability in an Enterocyte Cell Model 2024-03-18 , doi: 10.1002/anie.202317552 山一大团队：沙门氏菌操纵巨噬细胞，突破肠-血管屏障 EMBO Journal——[11.4] ① 肠道病原体沙门氏菌在侵袭肠道上皮细胞后迅速进入血液循环，山东第一医科大学的李冰清和陈启鑫团队发表文章，揭示了沙门氏菌在早期感染时通过操控CX3CR1+巨噬细胞迁移来穿透肠-血管屏障，进入血液循环；② 沙门氏菌依赖于宿主细胞的肌动蛋白和病原体效应蛋白SteC来诱导巨噬细胞的迁移/侵袭特性；③ SteC招募宿主肌球蛋白轻链蛋白Myl12a并磷酸化其Ser19和Thr20残基，Myl12a的磷酸化导致肌动蛋白重排，增强了巨噬细胞的迁移和侵袭能力；④ SteC能够利用多种NTPs，而不仅仅是ATP，对Myl12a进行磷酸化；⑤ 解析了SteC的晶体结构，揭示了其非典型的二聚体介导的催化机制，并证实了SteC介导的细胞骨架操控对沙门氏菌穿透肠血管屏障和扩散至靶器官至关重要。 【原文信息】 Salmonella manipulates macrophage migration via SteC-mediated myosin light chain activation to penetrate the gut-vascular barrier 2024-03-25 , doi: 10.1038/s44318-024-00076-7 CD4+CD8αα+肠道上皮内淋巴细胞发育的途径和机制（综述） Trends in Immunology——[16.8] ① CD4+CD8αα+T细胞是由成熟的CD4+ T细胞通过转录因子重编程分化而来，在小肠上皮中具有独特的发育途径；② 微生物代谢产物、细胞因子、MHC-II及其他细胞表面分子的共同作用促进了CD4+ T细胞向CD4+CD8αα+ T细胞的表型和功能转变；③ CD4+CD8αα+ T细胞兼具CD4+辅助T细胞和CD8+细胞毒性T细胞的标志物和分子，并具有广泛的免疫调节功能，从肠上皮细胞的细胞溶解到肠黏膜的免疫抑制，其功能可能取决于不同的环境条件，有待进一步研究。 【原文信息】 Pathways and mechanisms of CD4+CD8αα+ intraepithelial T cell development 2024-03-20 , doi: 10.1016/j.it.2024.02.006 中性粒细胞促进结直肠癌中血管生成 Journal of Clinical Investigation——[15.9] ① 这项研究揭示了中性粒细胞（PMN）在结直肠癌（CRC）中的组织特异性重编程，导致其促进肿瘤的血管生成；② 通过对血液和组织中性粒细胞的转录组分析，发现定位于外周血液、炎症性结肠和肿瘤的PMN三者的转录程序有明显差别；③ 肿瘤相关中性粒细胞（TANs）独特地富集血管生成和血管发育途径，且体外培养、结肠炎诱导的小鼠CRC和患者来源的异种移植模型等功能研究证明TANs在促进肿瘤血管化中具有关键作用；④ Spp1和Mmp14在TANs中高度诱导，对内皮细胞趋化和分支有关键调控作用；⑤ TCGA数据集和临床标本证实了SPP1和MMP14在高级别CRC患者中的富集，但在UC患者中并不富集；⑥ 使用药理学抑制TANs迁移或MMP14活性有效减少肿瘤血管密度，导致结直肠癌消退。 【原文信息】 Tissue-specific reprogramming leads to angiogenic neutrophil specialization and tumor vascularization in colorectal cancer 2024-02-08 , doi: 10.1172/JCI174545 Cell子刊：衰老细胞与巨噬细胞合作促进果蝇肠道转化 Developmental Cell——[11.8] ① 本研究探索体内如何整合多种诱导衰老信号来驱动仅少数细胞的衰老机制；② 在果蝇肠道转化模型中，AKT、JNK和DNA损伤信号同时激活导致部分细胞表现出多种衰老特征；③ 通过遗传手段或使用衰老细胞清除剂消除衰老细胞，可减少组织过度生长并提高存活率；④ 衰老细胞通过招募果蝇巨噬细胞到转化组织中，导致JNK信号的非自主激活，从而促进肿瘤发生；⑤ 本研究揭示了在果蝇肠道转化模型中，衰老细胞通过与巨噬细胞的相互作用，通过多激酶信号网络促进肠道转化的新机制。 【原文信息】 Senescent cells and macrophages cooperate through a multi-kinase signaling network to promote intestinal transformation in Drosophila 2024-01-31 , doi: 10.1016/j.devcel.2024.01.009 土壤细菌定植昆虫肠道激活免疫系统的奇妙之旅 PNAS——[11.1] ① 昆虫缺乏获得性免疫，也曾被认为没有免疫记忆，但最近的研究报道了“免疫印记”现象，即低剂量的病原体或非病原微生物刺激免疫并预防病菌感染，但其潜在机制尚不清楚；② PNAS发表的研究性论文揭示了摄入特定的土壤细菌Burkholderia能够穿透豆虫Riptortus pedestris的前肠道上皮细胞，迁移到体液中，从而激活系统性免疫，包括体液和细胞免疫反应；③ 这种激活的免疫反应不仅不会对宿主的健康产生负面影响，反而能够保护昆虫免受后续的病原细菌感染；④ 研究还发现，一旦中断了Burkholderia菌株与肠道上皮细胞的接触，宿主的免疫力会回落到感染前的水平，使昆虫更容易受到微生物感染，说明持续获取环境细菌对于维持有效免疫至关重要。 【原文信息】 Ingested soil bacteria breach gut epithelia and prime systemic immunity in an insect 2024-03-04 , doi: 10.1073/pnas.2315540121 LISCure活菌药LB-P8治疗PSC获FDA快速通道资格认定 ① 3月29日，LISCure Biosciences公司宣布，旗下治疗原发性硬化性胆管炎（PSC）活菌药LB-P8获得FDA快速通道资格认定；② LB-P8是目前在治疗PSC上唯一报告进入临床开发阶段的活菌药产品；③ LB-P8已在2022年获得治疗PSC的孤儿药资格认定，目前正处于2期临床研究阶段；④ LISCure Biosciences公司计划在美国和欧洲多个医疗机构开展该临床研究，并预计在2025年初获得初步结果。 【原文信息】 LISCure Biosciences receives U.S. FDA Fast Track designation for LB-P8 for the treatment of primary sclerosing cholangitis (PSC) 2024-03-29 , CISION Affibody PET显像剂ABY-025 2期临床首例胃食管癌患者入组 ① 3月26日，Affibody AB公司宣布，旗下PET/CT显像剂ABY-025，其2期临床试验的首例胃食管癌患者完成入组；② 胃食管癌早期诊断和治疗仍然是医学界面临的难题之一，患者HER2基因表达水平是衡量患者能否从靶向治疗中获益的重要标志；③ 使用ABY-025进行PET/CT成像，可以在注射后3-4小时确认肿瘤HER2基因表达水平的高低，从而预测靶向药物治疗效果；④ 研究还将比较PET/CT成像与组织活检获得的HER2表达水平数据 ，从而评估这一靶向检测手段能否带来新的治疗契机。 【原文信息】 FIRST GASTROESOPHAGEAL CANCER PATIENTS ENROLLED IN PHASE 2 BASKET TRIAL USING AFFIBODY’S PET IMAGING AGENT ABY-025 2024-03-28 , Affibody 瀚科迈博创新药HuA21 1b/2期临床完成首例患者入组 ① 3月29日，瀚科迈博自主研发的1类创新药HuA21注射液，其1b/2期临床试验完成首例受试者入组；② 该研究旨在评估HuA21注射液联合曲妥珠单抗化疗，治疗HER2阳性胃癌患者的安全性、耐受性和有效性；③ 该研究由复旦大学附属中山医院刘天舒教授和安徽医科大学第一附属医院孙倍成教授共同牵头；④ HuA21在1期临床试验中展现了优异的抗肿瘤活性，有望成为改变现阶段治疗方案的新药，瀚科迈博具有完全自主知识产权。 【原文信息】 瀚科迈博创新药HuA21注射液 Ib/II 期临床研究完成首例受试者入组 2024-03-29 , 安科生物 加科思JAB-30355片临床试验申请获CDE受理 ① 3月28日，北京加科思新药研发有限公司宣布其1类新药JAB-30355片的临床试验申请获国家药品审评中心（CDE）受理；② JAB-30355片是一款针对P53 Y220C的激活剂，用于治疗局部晚期或转移性实体瘤；③ 研究表明，JAB-30355片在多种肿瘤模型中实现了肿瘤消退，包括胃癌、乳腺癌和肺癌等；④ 该药物在美国已获批新药研究申请（IND），将开展针对晚期实体瘤的1/2a期临床试验；⑤ 此外，加科思布局了KRAS G12C抑制剂、SHP2抑制剂、BET抑制剂、GUE抑制剂等多款在研项目。 【原文信息】 加科思「P53 Y220C激活剂」在华申报临床 2024-03-29 , 药智新闻 飞鹤取得加拿大首张婴幼儿配方奶粉生产执照 ① 近日，飞鹤旗下加拿大皇家妙克公司获得加拿大食品检验局（CFIA）批准生产婴幼儿配方奶粉许可；② 该公司计划今年夏天将产品推向加拿大当地零售分销渠道；③ 飞鹤在加拿大的奶粉生产工厂是当地第一家婴幼儿配方奶粉生产企业，且在投产后也是加拿大当地生产、销售的第一个奶粉品牌；④ 2016年年底，飞鹤与加拿大金斯顿市签约，拟在该市投资建厂，该厂于2017年6月份开建，2019年调试完成。 【原文信息】 飞鹤取得加拿大首张婴幼儿配方奶粉生产执照 2024-03-29 , FoodTalks 感谢本期日报的审核者：章台柳，九卿臣，RZN，注册营养师陈彬林，圆圈儿，好雨，Richard，Alex Zhang 点击阅读过去10天的日报： 0401 | 3月，最值得关注的35篇肠道健康要闻！ 0331 | 聚焦特殊人群：老年人和孕妈妈的饮食新知 0330 | Akk菌或是免疫性肾病帮凶？Science子刊揭示机制 0329 | 33页综述纵论：超加工食品健康转型的新策略 0328 | Science子刊：锁定肠道中让病毒逃脱免疫的"避风港" 0327 | 10文聚焦菌群-肠-脑轴研究新进展 0326 | 100分综述详解：IBD细胞因子疗法最前沿 0325 | 大肠癌患病为何年轻化？遗传与生活方式的双重影响 0324 | 大型临床试验：补钙补D如何影响老年女性长期健康？ 0323 | Lancet+JAMA领衔，聚焦炎症性肠病诊断与治疗

Phase 1/2 study of KB-0742 is on track to clear 80mg four-days-on, three-days-off schedule in the third quarter of 2024; topline data from expansion cohort at this schedule expected in the first half of 2025 IND-enabling studies for KB-9558 expected to complete in 2024 with first-in-human study anticipated to commence in the first half of 2025 $175.0 million in cash, cash equivalents and investments as of December 31, 2023, providing expected cash runway into the second half of 2026 SAN MATEO, Calif. and CAMBRIDGE, Mass., March 21, 2024 (GLOBE NEWSWIRE) -- Kronos Bio Inc (Nasdaq: KRON), a company dedicated to transforming the lives of those affected by cancer, today reported recent business progress and fourth-quarter and full-year 2023 financial results. “In 2023, we made great progress across our portfolio and business. We demonstrated that KB-0742 has a safety pro is clearly differentiated from all other CDK9 inhibitors, and we believe our extended dosing schedule will show increased efficacy signals while maintaining a favorable safety profile,” said Nobert Bischofberger, Ph.D., president and chief executive officer of Kronos Bio. “We also announced our second development candidate, KB-9558, which is designed to target the KAT domain of p300 and downregulate IRF4 transcription in multiple myeloma. We are looking forward to completing the IND-enabling studies in 2024 and expect to dose our first patients in the first half of 2025.” Clinical Program and Recent Company Updates KB-0742 At the 2023 AACR-NCI-EORTC International Conference, the Company reported target engagement, tumor regressions, and an acceptable safety pro KB-0742 dosed at 60mg three-days-on, four-days-off in heavily pre-treated patients with transcriptionally addicted solid tumors. Out of fourteen “all-comer” patients, two patients with myxoid liposarcoma exhibited tumor regressions: one (7th line) had a partial response (per RECIST v1.1) lasting 113 days and the second achieved a 26% reduction in tumor diameters with stable disease. KB-0742 also cleared the 80mg three-days-on, four-days-off schedule in dose escalation and is currently enrolling patients in the KB-0742 60mg four-days-on, three-days-off dose escalation cohort of the Phase 1/2 trial. At a medical conference in mid-2024, the Company intends to share an update on the clinical data to date from patients with transcriptionally addicted tumors who were dosed with 60mg three-days-on, four-days-off, and from “all-comer” patients in the dose-escalation cohort who received 80mg three-days-on, four-days-off. In the third quarter of 2024, the Company expects to clear the 80mg four-days-on, three-days-off dose escalation cohort, and begin enrolling patients in an expansion cohort including one or more of the following: non-small cell lung cancer, small cell lung cancer, ovarian cancer, and triple negative breast cancer. The Company expects to announce topline data from the expansion cohort at the 80mg four-days-on, three-days-off dose in the first half of 2025. KB-9558 In December 2023, the Company announced the nomination of KB-9558, a p300 KAT inhibitor, as a development candidate. KB-9558 is the second development candidate to emerge from Kronos Bio’s product engine, where the Company identified that inhibition of the lysine acetyltransferase (KAT) domain on p300 inhibits expression of interferon regulatory factor 4 (IRF4) and thus collapses the transcription regulatory network that is required for the survival of multiple myeloma cells. The Company plans to present data on KB-9558 at the American Association for Cancer Research (AACR) annual meeting, being held from April 5-10, 2024 in San Diego, California, including how targeting p300’s enzymatic KAT domain can selectively downregulate IRF4. Pending completion of IND-enabling studies in 2024, the Company intends to initiate a first-in-human trial in relapsed or refractory multiple myeloma in the first half of 2025. Lanraplenib In December 2023, after a review of data from the Phase 1b portion of its Phase 1b/2 trial of lanraplenib in combination with gilteritinib in FLT3-mutated relapsed/refractory acute myeloid leukemia (AML), the Company decided not to proceed to Phase 2. Company Update Kronos Bio extended its expected cash runway by a year, into the second half of 2026, through restructurings and resource optimization. Fourth-Quarter and Full-Year 2023 Financial Highlights Cash, Cash Equivalents and Investments: With its ongoing and currently planned clinical programs and $175.0 million in cash, cash equivalents and investments as of December 31, 2023, the Company anticipates sufficient resources to fund its planned operations into the second half of 2026. R&D Expenses: Research and development expenses were $18.7 million for the fourth quarter of 2023, which includes non-cash stock-based compensation expense of $2.5 million. For the full year of 2023, research and development expenses were $86.4 million, which includes non-cash stock-based compensation expense of $12.0 million. G&A Expenses: General and administrative expenses were $10.9 million for the fourth quarter of 2023, which includes non-cash stock-based compensation expense of $2.7 million. For the full year of 2023, general and administrative expenses were $41.7 million, which includes non-cash stock-based compensation expense of $13.0 million. Net Loss: Net loss for the fourth quarter of 2023 was $25.3 million, or $0.43 per share, including non-cash stock-based compensation expense of $5.2 million. Net loss for the full-year 2023 was $112.7 million, or $1.95 per share, including non-cash stock-based compensation expense of $25.0 million. About Kronos Bio, Inc. Kronos Bio is a biopharmaceutical company that is advancing an investigational CDK9 inhibitor compound, KB-0742, in a Phase 1/2 clinical trial as a treatment for MYC-amplified solid tumors and other transcriptionally addicted solid tumors as well as a preclinical development candidate, KB-9558, targeting the KAT domain of p300 for multiple myeloma. The Company’s scientific focus is on developing medicines that target deregulated transcription, the hallmark of cancer and other serious diseases. Kronos Bio is based in San Mateo, Calif., and has a research facility in Cambridge, Mass. For more information, visit or follow the Company on LinkedIn. Forward-Looking Statements Statements in this press release that are not statements of historical fact are forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The press release, in some cases, uses terms such as “anticipate,” “believe,” “could,” “expect,” “on track,” “plan,” “potential,” “promising,” “will,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements include statements regarding Kronos Bio’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, the Phase 1/2 study of KB-0742 being on track to clear 80mg four-days-on, three-days-off schedule in Q3 2024; expected clinical results from the KB-0742 study; the expected timing for additional clinical data from the Phase 1/2 KB-0742 study; the potential completion of IND-enabling studies and the initial of a clinical trial for KB-9558 and the timing thereof; future pipeline development activities or outcomes; the potential of Kronos Bio’s product candidates; Kronos Bio’s expected cash runway; and other statements that are not historical fact. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: risks associated with changes to the assumptions underlying estimated expenses and savings; changes in the macroeconomic environment or competitive landscape that impact Kronos Bio’s business; whether Kronos Bio will be able to progress its clinical trials on the timelines anticipated, including due to risks inherent in the clinical development of novel therapeutics; risks related to Kronos Bio’s limited experience as a company in conducting clinical trials; the risk that results of preclinical studies and early clinical trials (including preliminary results) are not necessarily predictive of future results; and risks associated with the sufficiency of Kronos Bio’s cash resources and need for additional capital. These and other risks are described in greater detail in Kronos Bio’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in its Quarterly Report on Form 10-Q for the quarter ended September 30, 2023, filed with the SEC on November 13, 2023, and in its Annual Report on Form 10-K for the year ended December 31, 2023, being filed with the SEC today. Any forward-looking statements that are made in this press release speak only as of the date of this press release and are based on management’s assumptions and estimates as of such date. Except as required by law, Kronos Bio assumes no obligation to update the forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release. Kronos Bio, Inc. Statements of Operations and Comprehensive Loss (in thousands, except per share data) (Unaudited) Three Months Ended December 31, Year Ended December 31, 2023 2022 2023 2022 Revenue $ 2,286 $ — $ 6,288 $ — Operating expenses: Research and development 18,704 23,168 86,379 93,715 General and administrative 10,926 10,514 41,739 43,400 Total operating expenses 29,630 33,682 128,118 137,115 Loss from operations (27,344 ) (33,682 ) (121,830 ) (137,115 ) Other income (expense), net: Interest and other income, net 2,024 1,900 9,157 3,911 Total other income (expense), net 2,024 1,900 9,157 3,911 Net loss (25,320 ) (31,782 ) (112,673 ) (133,204 ) Other comprehensive income (loss): Net unrealized gain (loss) on available-for-sale securities 274 258 811 (753 ) Net comprehensive loss $ (25,046 ) $ (31,524 ) $ (111,862 ) $ (133,957 ) Net loss per share, basic and diluted $ (0.43 ) $ (0.56 ) $ (1.95 ) $ (2.37 ) Weighted-average number of shares used to compute net loss per share, basic and diluted 58,268 56,523 57,744 56,201 Kronos Bio, Inc. Selected Balance Sheet Data (in thousands) (Unaudited) December 31, 2023 December 31, 2022 Cash, cash equivalents and investments $ 174,986 $ 247,947 Total assets $ 213,279 $ 294,938 Total liabilities $ 54,201 $ 50,439 Total stockholders’ equity $ 159,078 $ 244,499 Investor & Media Contact: Margaux Bennett Vice President, Corporate Development and Investor Relations, Kronos Bio 650-781-5026 mbennett@kronosbio.com