rational drug design

合理的药物设计
  • 文章类型: Journal Article
    由于其稳定性和特异性,环肽已成为药物发现中的通用支架。这里,我们介绍了cPEPmatch网络服务器(可在https://t38webservices访问。nat.tum.de/cpepmatch/),一个易于使用的界面,用于合理设计靶向蛋白质-蛋白质相互作用的环肽,并结合结合稳定性的半定量评估。该平台还提供对环状肽晶体结构的综合数据库的访问。我们通过一系列涉及医学相关蛋白质系统的案例研究来证明网络服务器的实用性,强调其显著推进药物发现工作的潜力。
    Cyclic peptides have emerged as versatile scaffolds in drug discovery due to their stability and specificity. Here, we present the cPEPmatch webserver (accessible at https://t38webservices.nat.tum.de/cpepmatch/), an easy-to-use interface for the rational design of cyclic peptides targeting protein-protein interactions combined with a semi-quantitative evaluation of binding stability. This platform also offers access to a comprehensive database of cyclic peptide crystal structures. We demonstrate the webserver\'s utility through a series of case studies involving medically relevant protein systems, highlighting its potential to significantly advance drug discovery efforts.
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  • 文章类型: Journal Article
    背景:新底物的靶向蛋白质降解在涉及免疫调节酰亚胺药物(IMiDs)治疗的血液癌症治疗中起着至关重要的作用。然而,不可避免的耐药性和血液毒性的持续存在是其临床有效性的重大障碍。
    方法:对多种血液癌细胞系中的小分子化合物文库进行表型分析以筛选命中降解物。进行基于分子动力学的合理设计和基于细胞的功能测定以开发更有效的降解剂。采用多发性骨髓瘤(MM)肿瘤异种移植模型来研究降解剂作为单一药剂或与标准护理剂组合的抗肿瘤功效。无偏蛋白质组学用于鉴定降解剂靶向的多种治疗相关的新底物。MM患者来源的细胞系(PDC)和一组实体癌细胞系用于研究候选降解剂对MM细胞和实体恶性肿瘤的不同阶段的影响。IMiDs抗性MM细胞的无偏蛋白质组学,基于细胞的功能测定和临床MM标本的RT-PCR分析被用来探讨BRD9与IMiDs耐药和MM进展相关的作用.
    结果:我们确定了一种新型的依赖ceblon(CRBN)的铅降解剂,MGD-4诱导Ikaros蛋白降解。我们进一步开发了一种新的有效候选人,MGD-28显着抑制血液癌细胞的生长,并通过Cullin-CRBN依赖性途径以纳摩尔效价诱导IKZF1/2/3和CK1α的降解。MGD-4和MGD-28的口服施用有效地抑制MM肿瘤生长,并且表现出与标准护理剂的显著协同作用。MGD-28在不同疾病阶段优先表现出对MMPDC的深刻细胞毒性,并在多种实体恶性肿瘤中表现出广泛的抗增殖活性。BRD9调制IMiDs电阻,不同分期MM标本中BRD9的表达与IKZF1/2/3和CK1α呈显著正相关。我们还观察到BRD9抑制剂和MGD-28之间对于MM治疗的显著协同功效。
    结论:我们的发现提出了一种针对血液肿瘤的Ikaros蛋白和CK1α的多靶向降解策略,可以扩展到其他目标和适应症。该策略可以增强针对多种血液癌症和实体瘤的功效治疗。
    BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness.
    METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression.
    RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment.
    CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.
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  • 文章类型: Journal Article
    HIV衣壳(CA)蛋白是抗AIDS治疗的有希望的靶标,因为它与病毒复制密切相关。在这里,我们使用有据可查的CA抑制剂PF74作为先导化合物,并设计了一系列低分子量苯丙氨酸衍生物.其中,化合物7t表现出显著的抗病毒活性,具有高选择指数(EC50=0.040µM,SI=2815),超过PF74(EC50=0.50µM,SI=258)。此外,当针对HIV-2株进行评估时,7t(EC50=0.13µM)的效力比PF74(EC50=1.76µM)高约14倍。从表面等离子体共振(SPR)获得的见解表明,与PF74相比,7t对CA六聚体和单体表现出更强的靶标亲和力。使用分子对接和分子动力学模拟进一步阐明了7t与HIV-1CA之间的潜在相互作用,为7t比PF74增强的靶标亲和力提供了合理的解释。此外,代谢稳定性分析表明,7t(T1/2=77.0分钟)显着优于PF74(T1/2=0.7分钟)在人肝微粒体,表现出110倍的改进系数。总之,7t成为有希望的候选药物,值得进一步研究。
    The HIV capsid (CA) protein is a promising target for anti-AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well-documented CA inhibitor PF74 as our lead compound and designed a series of low-molecular-weight phenylalanine derivatives. Among them, compound 7t exhibited remarkable antiviral activity with a high selection index (EC50 = 0.040 µM, SI = 2815), surpassing that of PF74 (EC50 = 0.50 µM, SI = 258). Furthermore, when evaluated against the HIV-2 strain, 7t (EC50 = 0.13 µM) demonstrated approximately 14-fold higher potency than that of PF74 (EC50 = 1.76 µM). Insights obtained from surface plasmon resonance (SPR) revealed that 7t exhibited stronger target affinity to the CA hexamer and monomer in comparison to PF74. The potential interactions between 7t and the HIV-1 CA were further elucidated using molecular docking and molecular dynamics simulations, providing a plausible explanation for the enhanced target affinity with 7t over PF74. Moreover, the metabolic stability assay demonstrated that 7t (T1/2 = 77.0 min) significantly outperforms PF74 (T1/2 = 0.7 min) in human liver microsome, exhibiting an improvement factor of 110-fold. In conclusion, 7t emerges as a promising drug candidate warranting further investigation.
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  • 文章类型: Journal Article
    危及生命的系统性真菌感染在免疫功能低下的患者中以惊人的速度发生。目前的抗真菌治疗面临的挑战,如耐药性和患者的毒性,强调需要新的治疗方法。膜结合酶在当前和潜在的抗真菌靶标中占很大比例,特别是那些有助于细胞壁和细胞膜生物合成的物质。此外,结构生物学使人们对这些酶合成其产物的机制有了更好的理解,以及一些抗真菌药物的作用机制。这篇综述总结了与细胞壁和细胞膜生物合成有关的几种当前和潜在的膜结合抗真菌靶标的结构,以及它们与已知抑制剂或药物的相互作用。一些分子的作用机制,从详细的抑制剂蛋白研究中收集到,还描述了,这有助于进一步合理的药物设计。此外,一些潜在的膜结合抗真菌靶标与已知的抑制剂,缺乏解决的结构进行了讨论,因为这些可能是未来结构询问的好酶。
    Life-threatening systemic fungal infections occur in immunocompromised patients at an alarming rate. Current antifungal therapies face challenges like drug resistance and patient toxicity, emphasizing the need for new treatments. Membrane-bound enzymes account for a large proportion of current and potential antifungal targets, especially ones that contribute to cell wall and cell membrane biosynthesis. Moreover, structural biology has led to a better understanding of the mechanisms by which these enzymes synthesize their products, as well as the mechanism of action for some antifungals. This review summarizes the structures of several current and potential membrane-bound antifungal targets involved in cell wall and cell membrane biosynthesis and their interactions with known inhibitors or drugs. The proposed mechanisms of action for some molecules, gleaned from detailed inhibitor-protein studeis, are also described, which aids in further rational drug design. Furthermore, some potential membrane-bound antifungal targets with known inhibitors that lack solved structures are discussed, as these might be good enzymes for future structure interrogation.
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  • 文章类型: Journal Article
    在这项研究中,我们使用了计算机技术来确定可用的寄生虫治疗方法,代表着一个有希望的治疗途径。基于我们的计算计划,旨在发现来自寄生虫的各种靶酶的天然抑制剂,从而导致被忽视的热带病(NTDs),我们提出了关于三种姜黄衍生的植物化学物质作为利什曼原虫蝶啶还原酶I(PTR1)抑制剂的新发现。PTR1是锥虫寄生虫独特叶酸代谢的关键酶,具有既定的治疗意义。采用教育部软件,分子对接分析评估姜黄植物化学物质对抗利什曼原虫PTR1的功效。通过RMSD值为2来确认对接协议的验证。对接后,选择与关键残基显着相互作用的化合物以及在-6和-8kcal/mol之间的结合亲和力进行相互作用模式探索。测试十二种姜黄植物化学物质,包括姜黄素,ingiberene,curcumol,姜黄烯醇,丁香酚,双去甲氧基姜黄素,四氢姜黄素,三乙基姜黄素,姜黄酮,Turmerin,去甲氧基姜黄素,和turmeronols,显示结合亲和力范围为-5.5至-8kcal/mol。值得注意的是,姜黄素,去甲氧基姜黄素,和双去甲氧基姜黄素表现出-6.5至-8kcal/mol的结合亲和力,并与催化残基建立了实质性的相互作用。这些植物化学物质有望成为针对利什曼原虫的合理药物设计的先导结构。PTR在未来的应用中。这项工作强调了这些已确定的植物化学物质在开发更有效的抑制剂方面的潜力,证明了它们在解决由寄生虫引起的被忽视的热带病方面的相关性。
    In this study, we used in silico techniques to identify available parasite treatments, representing a promising therapeutic avenue. Building upon our computational initiatives aimed at discovering natural inhibitors for various target enzymes from parasites causing neglected tropical diseases (NTDs), we present novel findings on three turmeric-derived phytochemicals as inhibitors of Leishmania pteridine reductase I (PTR1) through in silico methodologies. PTR1, a crucial enzyme in the unique folate metabolism of trypanosomatid parasites, holds established therapeutic significance. Employing MOE software, a molecular docking analysis assesses the efficacy of turmeric phytochemicals against Leishmania PTR1. Validation of the docking protocol is confirmed with an RMSD value of 2. Post-docking, compounds displaying notable interactions with critical residues and binding affinities ranging between -6 and -8 kcal/mol are selected for interaction pattern exploration. Testing twelve turmeric phytochemicals, including curcumin, zingiberene, curcumol, curcumenol, eugenol, bisdemethoxycurcumin, tetrahydrocurcumin, tryethylcurcumin, turmerones, turmerin, demethoxycurcumin, and turmeronols, revealed binding affinities ranging from -5.5 to -8 kcal/mol. Notably, curcumin, demethoxycurcumin, and bisdemethoxycurcumin exhibit binding affinities within -6.5 to -8 kcal/mol and establish substantial interactions with catalytic residues. These phytochemicals hold promise as lead structures for rational drug design targeting Leishmania spp. PTR in future applications. This work underscores the potential of these identified phytochemicals in the development of more effective inhibitors, demonstrating their relevance in addressing neglected tropical diseases caused by parasites.
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  • 文章类型: Journal Article
    了解蛋白质序列和结构对于理解蛋白质-蛋白质相互作用(PPI)至关重要。这对许多生物过程和疾病至关重要。靶向蛋白质结合热点,调节信号和生长,与合理的药物设计是有希望的。合理的药物设计使用结构数据和计算工具来研究蛋白质结合位点和蛋白质界面,以设计可以改变这些相互作用的抑制剂,从而可能导致治疗方法。人工智能(AI)例如机器学习(ML)和深度学习(DL),通过提供计算资源和方法,具有先进的药物发现和设计。量子化学对药物反应至关重要,毒理学,药物筛选,和定量结构-活性关系(QSAR)特性。这篇综述讨论了识别和表征热点和结合位点的方法和挑战。它还探讨了基于人工智能的合理药物设计技术的策略和应用,这些技术靶向蛋白质和蛋白质-蛋白质相互作用(PPI)结合热点。它为具有治疗意义的药物设计提供了有价值的见解。我们还证明了热休克蛋白27(HSP27)和基质金属蛋白酶(MMP2和MMP9)的病理状况,并在发现用于癌症治疗的药物分子的案例研究中使用药物发现范例设计了这些蛋白质的抑制剂。此外,讨论了苯并噻唑衍生物对抗癌药物设计和发现的意义。
    Understanding protein sequence and structure is essential for understanding protein-protein interactions (PPIs), which are essential for many biological processes and diseases. Targeting protein binding hot spots, which regulate signaling and growth, with rational drug design is promising. Rational drug design uses structural data and computational tools to study protein binding sites and protein interfaces to design inhibitors that can change these interactions, thereby potentially leading to therapeutic approaches. Artificial intelligence (AI), such as machine learning (ML) and deep learning (DL), has advanced drug discovery and design by providing computational resources and methods. Quantum chemistry is essential for drug reactivity, toxicology, drug screening, and quantitative structure-activity relationship (QSAR) properties. This review discusses the methodologies and challenges of identifying and characterizing hot spots and binding sites. It also explores the strategies and applications of artificial-intelligence-based rational drug design technologies that target proteins and protein-protein interaction (PPI) binding hot spots. It provides valuable insights for drug design with therapeutic implications. We have also demonstrated the pathological conditions of heat shock protein 27 (HSP27) and matrix metallopoproteinases (MMP2 and MMP9) and designed inhibitors of these proteins using the drug discovery paradigm in a case study on the discovery of drug molecules for cancer treatment. Additionally, the implications of benzothiazole derivatives for anticancer drug design and discovery are deliberated.
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  • 文章类型: Journal Article
    背景:赖氨酸脱甲基酶(KDMs)是一类新兴的治疗靶标,催化从调节染色质结构和基因表达的组蛋白赖氨酸残基中去除甲基标记。KDM4A亚型在各种癌症的表观遗传失调中起重要作用,并与侵袭性疾病和不良临床结果有关。尽管做出了一些努力,KDM4家族缺乏成功的特异性分子抑制剂。
    结果:这里,从基于结构的片段虚拟筛查活动开始,我们开发了一个协同框架,作为合理设计有效的KDM4A抑制剂的指导。商业文库用于创建片段集合并进行结合对接和药效团方法的虚拟筛选活动。通过开发用于通过抑制H3K9me3肽去甲基化来鉴定选择性底物竞争性抑制剂的基于均相时间分辨荧光的测定法在体外测试了最有前途的化合物。2-(甲基氨基甲酰基)异烟酸被鉴定为初步活性片段,显示KDM4A酶活性的抑制。通过计算和实验方法对其化学探索进行了深入研究,从而实现了合理的碎片生长过程。计算机内研究指导了设计为主要片段命中扩展的衍生物的开发,并提供了有关结构-活性关系的进一步知识。
    结论:我们的研究描述了对关键配体-KDM4A蛋白相互作用的有用见解,并为开发成功的选择性KDM4A抑制剂提供了结构特征。
    Lysine demethylase enzymes (KDMs) are an emerging class of therapeutic targets, that catalyse the removal of methyl marks from histone lysine residues regulating chromatin structure and gene expression. KDM4A isoform plays an important role in the epigenetic dysregulation in various cancers and is linked to aggressive disease and poor clinical outcomes. Despite several efforts, the KDM4 family lacks successful specific molecular inhibitors.
    Herein, starting from a structure-based fragments virtual screening campaign we developed a synergic framework as a guide to rationally design efficient KDM4A inhibitors. Commercial libraries were used to create a fragments collection and perform a virtual screening campaign combining docking and pharmacophore approaches. The most promising compounds were tested in-vitro by a Homogeneous Time-Resolved Fluorescence-based assay developed for identifying selective substrate-competitive inhibitors by means of inhibition of H3K9me3 peptide demethylation. 2-(methylcarbamoyl)isonicotinic acid was identified as a preliminary active fragment, displaying inhibition of KDM4A enzymatic activity. Its chemical exploration was deeply investigated by computational and experimental approaches which allowed a rational fragment growing process. The in-silico studies guided the development of derivatives designed as expansion of the primary fragment hit and provided further knowledge on the structure-activity relationship.
    Our study describes useful insights into key ligand-KDM4A protein interaction and provides structural features for the development of successful selective KDM4A inhibitors.
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  • 文章类型: Journal Article
    使用单个分子同时抑制PI3K和组蛋白脱乙酰酶(HDAC)活性似乎是一种有希望的癌症治疗方法。目前的PI3K/HDAC双重抑制剂通常使用异羟肟酸部分作为锌结合基团,缺乏HDAC同工型选择性并具有潜在的遗传毒性。在这项研究中,合理设计和合成了一系列基于苯甲酰胺的PI3K/HDAC双重抑制剂。代表性化合物PH14对PI3Kα和HDAC3显示出有效的抑制活性,IC50值为20.3nM和24.5nM,分别。蛋白质印迹研究中AKT磷酸化的阻断和乙酰化组蛋白H3水平的增加进一步支持了这一点。同时靶向PI3Kα和HDAC的优势不仅体现在显著的抗增殖活性,而且还具有促进Jeko-1细胞凋亡的能力。此外,PH14对CYP450酶和hERG的抑制作用较弱。在药代动力学研究中,给予1mg/kg的PH14,给予1mg/kg的PH14导致10h的t1/2和2772hng/mL的AUC(0-∞)。本研究可为进一步开发新型HDAC/PI3K双重抑制剂提供思路。
    Inhibition of PI3K and histone deacetylase (HDAC) activity simultaneously using a single molecule appears to be a promising approach for cancer treatment. Current PI3K/HDAC dual inhibitors commonly use hydroxamate moiety as zinc binding group, which lack HDAC isoform selectivity and have potential genotoxicity. In this study, a novel series of benzamide-based PI3K/HDAC dual inhibitors were rationally designed and synthesized. Representative compound PH14 showed potent inhibitory activity toward PI3Kα and HDAC3, with IC50 values of 20.3 nM and 24.5 nM, respectively. This was further supported by the blockage of AKT phosphorylation and an increase in acetylated histone H3 levels in Western blot study. The advantage of simultaneously targeting PI3Kα and HDAC is not only reflected in the significant antiproliferative activity, but also in its ability to promote the apoptosis in Jeko-1 cells. Moreover, PH14 had weak inhibitory effects on CYP450 enzymes and hERG. In the pharmacokinetic study, the administration of 1 mg/kg of PH14 the administration of 1 mg/kg of PH14 resulted in a t1/2 of 10 h and an AUC (0-∞) of 2772 h ng/mL. Our study may provide ideas for the further development of novel HDAC/PI3K dual inhibitors.
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  • 文章类型: Journal Article
    神经系统疾病在治疗方案方面提出了重大挑战,有必要探索新的治疗方法。Trigonelline,一种在各种植物中发现的天然生物碱,已经成为一种潜在的治疗选择。也有报道称,芦竹碱参与了几种途径,如:氧化应激和抗氧化剂,炎症,神经保护和神经营养,线粒体功能和能量代谢。本研究旨在使用分子对接方法研究Trigonelline对多种神经系统疾病的治疗潜力。进行分子对接模拟以预测在神经系统疾病中涉及的三角碱和靶蛋白之间的结合亲和力和相互作用。还探讨了有效结合的结构要求。分子对接结果揭示了与多种神经系统疾病(如阿尔茨海默病)有关的Trigonelline和靶蛋白之间的强结合相互作用和良好的结合亲和力。帕金森病,癫痫,抑郁症等。预测的结合模式提供了对控制配体-蛋白质复合物的关键分子相互作用的见解。研究结果表明,Trigonelline有望作为几种神经系统疾病的治疗方法。本研究中采用的分子对接方法为基于三角碱的化合物的合理药物设计和优化提供了有价值的工具。进一步的实验验证和临床前研究是必要的,以确认的疗效和安全性,作为一个潜在的治疗选择,为开发更有效和有针对性的神经系统疾病疗法铺平了道路。
    Neurological disorders pose significant challenges in terms of treatment options, necessitating the exploration of novel therapeutic approaches. Trigonelline, a naturally occurring alkaloid found in various plants, has emerged as a potential treatment option. It has also been reported that trigonelline is involved in several pathways like; Oxidative Stress and Antioxidant, Inflammatory, Neuroprotection and Neurotrophic, Mitochondrial Function and Energy Metabolism. This study aims to investigate the therapeutic potential of trigonelline for diverse neurological disorders using a molecular docking approach. Molecular docking simulations were performed to predict the binding affinity and interaction between trigonelline and target proteins implicated in neurological disorders. The structural requirements for effective binding were also explored. The molecular docking results revealed strong binding interactions and favorable binding affinities between trigonelline and the target proteins involved in diverse neurological disorders like Alzheimer\'s disease, Parkinson\'s disease, epilepsy, and depression etc. The predicted binding modes provided insights into the key molecular interactions governing the ligand-protein complexes. The findings suggest that trigonelline holds promise as a therapeutic approach for several neurological disorders. The molecular docking approach employed in this study provides a valuable tool for rational drug design and optimization of trigonelline-based compounds. Further experimental validation and preclinical studies are warranted to confirm the efficacy and safety of trigonelline as a potential treatment option, paving the way for the development of more effective and targeted therapies for neurological disorders.
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  • 文章类型: Journal Article
    I类PI3K的γ同种型(PI3Kγ)主要存在于白细胞中,对于骨髓细胞的功能至关重要。因为它调节了迁移,分化,和髓系免疫细胞的激活。因此,PI3Kγ已被确定为治疗炎症的有希望的药物靶标,自身免疫性疾病,和免疫肿瘤学。由于与PI3K抑制剂相关的严重不良事件(AE)的高发生率,在PI3Kγ抑制剂的开发中,同工型选择性被认为是至关重要的。在这次审查中,概述了过去几年PI3Kγ选择性抑制剂的发展。通过不同的策略实现了相关药物的同工型选择性,包括通过螺旋桨形结构诱导特异性口袋,靶向溶剂通道中的空间差异,调节Asp-Phe-GlyDFG基序的构象,几个成功的案例证明了这一点是可行的。本文的见解可能为合理的药物设计提供潜在的方向,并加速PI3Kγ选择性抑制剂的发现。
    The γ isoform of Class I PI3Ks (PI3Kγ) is primarily found in leukocytes and is essential for the function of myeloid cells, as it regulates the migration, differentiation, and activation of myeloid-lineage immune cells. Thus, PI3Kγ has been identified as a promising drug target for the treatment of inflammation, autoimmune disease, and immuno-oncology. Due to the high incidence of serious adverse events (AEs) associated with PI3K inhibitors, in the development of PI3Kγ inhibitors, isoform selectivity was deemed crucial. In this review, an overview of the development of PI3Kγ selective inhibitors in the past years is provided. The isoform selectivity of related drugs was achieved by different strategies, including inducing a specificity pocket by a propeller-shape structure, targeting steric differences in the solvent channel, and modulating the conformation of the Asp-Phe-Gly DFG motif, which have been demonstrated feasible by several successful cases. The insights in this manuscript may provide a potential direction for rational drug design and accelerate the discovery of PI3Kγ selective inhibitors.
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