The primary purpose of this study is to characterize the safety profile of BMS-986408 as monotherapy and in combination with nivolumab or nivolumab and ipilimumab to establish the maximum tolerated dose (MTD). The Recommended Phase 2 Dose (RP2D) that optimizes the pharmacokinetic/pharmacodynamic (PK/PD) relationship of BMS-986408 will also be determined.

开始日期2022-08-02

申办/合作机构

Bristol Myers Squibb Co.

100 项与 DGKA x DGKζ 相关的临床结果

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100 项与 DGKA x DGKζ 相关的转化医学

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0 项与 DGKA x DGKζ 相关的专利（医药）

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项与 DGKA x DGKζ 相关的文献（医药）

2018-06-01·Cancer Immunology, Immunotherapy2区 · 医学

Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals

2区 · 医学

Article

作者: Ogando, Jesús ; Mérida, Isabel ; Meraviglia-Crivelli, Daniel ; Arranz-Nicolás, Javier ; Mañes, Santos ; Arcos-Pérez, Raquel ; Soutar, Denise ; Ávila-Flores, Antonia

The arsenal of cancer therapies has evolved to target T lymphocytes and restore their capacity to destroy tumor cells. T cells rely on diacylglycerol (DAG) to carry out their functions. DAG availability and signaling are regulated by the enzymes diacylglycerol kinase (DGK) α and ζ, whose excess function drives T cells into hyporesponsive states. Targeting DGKα is a promising strategy for coping with cancer; its blockade could reinstate T-cell attack on tumors while limiting tumor growth, due to positive DGKα functions in several oncogenic pathways. Here, we made a side-by-side comparison of the effects of commercial pharmacological DGK inhibitors on T-cell responses with those promoted by DGKα and DGKζ genetic deletion or silencing. We show the specificity for DGKα of DGK inhibitors I and II and the structurally similar compound ritanserin. Inhibitor treatment promoted Ras/ERK (extracellular signal-regulated kinase) signaling and AP-1 (Activator protein-1) transcription, facilitated DGKα membrane localization, reduced the requirement for costimulation, and cooperated with enhanced activation following DGKζ silencing/deletion. DGKiII and ritanserin had similar effects on TCR proximal signaling, but ritanserin counteracted long-term T-cell activation, an effect that was potentiated in DGKα^-/- cells. In contrast with enhanced activation triggered by pharmacological inhibition, DGKα silencing/genetic deletion led to impaired Lck (lymphocyte-specific protein tyrosine kinase) activation and limited costimulation responses. Our results demonstrate that pharmacological inhibition of DGKα downstream of the TCR provides a gain-of-function effect that amplifies the DAG-dependent signaling cascade, an ability that could be exploited therapeutically to reinvigorate T cells to attack tumors.

2008-01-01·Frontiers in Bioscience

Nuclear diacylglycerol kinases: regulation and roles

Review

作者: Raben, Daniel M. ; Tu-Sekine, Becky

The diacylglycerol-kinases are a family of related lipid kinases. There are currently 10 known isoforms of diacylglycerol kinases that are categorized into five groups based on similarities in their primary sequence. All of these enzymes catalyze the transfer of the gamma-phosphate of ATP to one lipid second messenger, diacylglycerol, thereby generating another lipid second messenger, phosphatidic acid. As a result, they are uniquely poised to regulate the relative levels of these two key second messengers. These enzymes show considerable diversity in their cellular and sub-cellular distribution which suggests a great diversity in physiological functions. One sub-cellular compartment that is receiving a considerable attention is the nucleus. A number of DGKs have been found to reside in, or translocate to the nucleus in response to agonists. In this review we focus primarily on the nuclear localization, modulation of intrinsic enzymatic activity, and the potential physiological roles of the six diacylglycerol kinases that have been found in the nucleus: DGK-alpha, DGK-gamma, DGK-delta, DGK-zeta, DGK-iota, and DGK-theta.

2006-11-01·Nature Immunology1区 · 医学

Disruption of diacylglycerol metabolism impairs the induction of T cell anergy

1区 · 医学

Article

作者: Jeffery H. Carpenter ; Gary A. Koretzky ; Matthew K. Topham ; Martha Jordan ; Rishu Guo ; Xiao Ping Zhong ; Benjamin A. Olenchock

Anergic T cells have altered diacylglycerol metabolism, but whether that altered metabolism has a causative function in the induction of T cell anergy is not apparent. To test the importance of diacylglycerol metabolism in T cell anergy, we manipulated diacylglycerol kinases (DGKs), which are enzymes that terminate diacylglycerol-dependent signaling. Overexpression of DGK-alpha resulted in a defect in T cell receptor signaling that is characteristic of anergy. We generated DGK-alpha-deficient mice and found that DGK-alpha-deficient T cells had more diacylglycerol-dependent T cell receptor signaling. In vivo anergy induction was impaired in DGK-alpha-deficient mice. When stimulated in anergy-producing conditions, T cells lacking DGK-alpha or DGK-zeta proliferated and produced interleukin 2. Pharmacological inhibition of DGK-alpha activity in DGK-zeta-deficient T cells that received an anergizing stimulus proliferated similarly to wild-type T cells that received CD28 costimulation and prevented anergy induction. Our findings suggest that regulation of diacylglycerol metabolism is critical in determining whether activation or anergy ensues after T cell receptor stimulation.

项与 DGKA x DGKζ 相关的新闻（医药）

2024-06-21

·医药观澜

拜耳2款新药在中国获批临床，治疗癌症、脑卒中！

中国国家药监局药品审评中心（CDE）官网公示，近日拜耳（Bayer）公司申报的两款1类新药获得临床试验默示许可，分别拟用于治疗晚期实体瘤和急性缺血性脑卒中患者。根据拜耳公开资料，这两款新药分别为DGKα抑制剂和抗a2AP的蛋白质药物，在国际上分别处于1期和2期临床阶段。 BAY 2862789口服溶液：DGKα抑制剂适应症：晚期实体瘤 BAY 2862789口服溶液由拜耳与德国癌症研究中心（DKFZ）合作开发，为小分子DGKα抑制剂，目前在国际范围内处于1期首次人体研究阶段，拟开发治疗实体瘤。甘油二酯激酶（DGKs）家族被认为是T细胞和NK细胞发育、分化和功能的生理调节剂，在多种细胞信号传导通路中起着重要的调节作用。DGKα和DGKζ均是DGKs主要的亚型，二者在T细胞中的上调均会导致T细胞沉默。研究表明，DGKα在几种难治性肿瘤细胞中高表达，包括黑色素瘤、肝细胞癌、胶质母细胞瘤等，它能减缓细胞凋亡、促进细胞增殖。除癌细胞外，DGKα在T细胞中也非常丰富，并诱导T细胞沉默，这是晚期癌症逃过免疫作用的主要机制。因此，DGKα特异性抑制剂治疗癌症有望发挥抑制癌细胞增殖、同时激活T细胞功能的双重抗癌作用。此外，抑制DGKα可协同增强PD-1/L1的抗癌作用，为难治性癌症提供了一种有希望的新治疗策略。值得一提的是，拜耳与德国癌症研究中心（DKFZ）还合作开发了一款DGKζ抑制剂BAY 2965501，该产品已经于今年4月在中国获批临床。研究表明，联合抑制/沉默DGKα和DGKζ可协同刺激黑色素瘤细胞凋亡和T细胞中白细胞介素-2的产生，二者有望产生协同抗癌作用。 BAY 3018250：抗a2AP的蛋白质药物适应症：急性缺血性脑卒中血栓性血管闭塞是缺血性卒中的主要原因。α2-抗纤溶酶（a2AP）是一种纤溶酶抑制剂，为丝氨酸蛋白酶抑制剂家族的一员，与缺血性卒中、组织纤溶酶原激活剂（rt-PA）治疗失败的风险增加有关。抗a2AP治疗可显著减少血栓栓塞性卒中后微血管血栓形成、缺血性脑损伤、脑肿胀、脑出血和死亡，这些研究提示暂时失活a2AP可能对缺血性脑卒中具有治疗价值。 BAY 3018250是拜耳心血管疾病研发管线中的一员，为抗a2AP的蛋白质类药物，拟开发治疗急性缺血性卒中和肺栓塞。该产品在国际范围内目前正处于治疗深静脉血栓（DVT）的2期临床研究阶段。DVT会导致严重的健康问题，包括血凝块卡在肺部，阻碍血液流向肺部等。BAY3018250可以通过溶解血凝块起到治疗作用。本次BAY 3018250在中国获批临床，针对适应症为急性缺血性脑卒中。这意味着该产品即将在中国开展针对这种新适应症的临床研究。参考资料： [1]中国国家药监局药品审评中心（CDE）官网. Retrieved June 20，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [2]拜耳研发管线. . Retrieved Apr 30，2024, From https://www.bayer.com/sites/default/files/ph-rd-pipeline-2024-05-final-1.pdf [3]Sakane F, et al. (2021)The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis. Cancers (Basel). doi: 10.3390/cancers13205190. [4]Reed GL, Houng AK, Singh S, Wang D. （2017）α2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke. Semin Thromb Hemost. doi: 10.1055/s-0036-1585077. 内容来源于网络，如有侵权，请联系删除。