A Phase Ib Study, Evaluating the Safety, Tolerance and Efficacy of PRJ1-3024 Capsules in China Subjects with Unresectable Local Advanced or Metastatic Melanoma

This is a Phase Ib, open-label study to determine the safety and preliminary efficacy of PRJ1-3024 in China subjects with unresectable local advanced or metastatic melanoma

开始日期2024-03-14

申办/合作机构

广州宇繁南图生物科技有限公司

CTR20240751

/ Recruiting临床1期

一项评价PRJ1-3024胶囊在不可切除性局部晚期或者转移性黑色素瘤患者中疗效、安全性和耐受性的Ib期临床研究

主要目的评价PRJ1-3024胶囊（以下称PRJ1-3024）在不可切除性局部晚期或者转移性黑色素瘤受试者中的初步疗效；确定PRJ1-3024在不可切除性局部晚期或者转移性黑色素瘤受试者中的II期临床推荐剂量（RP2D）。次要目的评价PRJ1-3024在不可切除性局部晚期或者转移性黑色素瘤受试者中的安全性和耐受性；评价PRJ1-3024在不可切除性局部晚期或者转移性黑色素瘤受试者中的药代动力学（PK）特征。探索性目的探索可能提示PRJ1-3024在不可切除性局部晚期或者转移性黑色素瘤受试者中疗效的药效学生物标志物。

开始日期2024-03-14

申办/合作机构

广州宇繁南图生物科技有限公司

NCT05315167

/ Recruiting临床1/2期

A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Prime Efficacy of PRJ1-3024 in Subjects with Advanced Solid Tumors

This is a multicenter, open-label study to assess the safety and preliminary efficacy and to determine the maximum tolerated dose (MTD) or maximum administration dose (MAD) and recommended Phase 2 doses (RP2D) of PRJ1-3024 in subjects with relapsed/refractory solid tumors. The study consists of two parts, one is a 3+3 dose escalation study and another is a pharmaceutical extension of RP2D.

开始日期2022-05-30

申办/合作机构

广州宇繁南图生物科技有限公司

100 项与广州宇繁南图生物科技有限公司相关的临床结果

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0 项与广州宇繁南图生物科技有限公司相关的专利（医药）

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项与广州宇繁南图生物科技有限公司相关的文献（医药）

2025-06-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Rational design, optimization, and biological evaluation of novel pyrrolo-pyridone derivatives as potent and orally active Cbl-b inhibitors

Article

作者: Chai, Yushuang ; Zhang, Yixuan ; Guan, Xiangna ; An, Na ; Lu, Tingting ; Liao, Xuebin ; Lin, Xinyu

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, plays a critical role in negatively regulating T-cell, natural killer (NK) cell, and B-cell activation. Inhibiting Cbl-b has emerged as a promising immuno-oncology strategy to enhance immune cell function. Here, we describe the rational design and optimization of pyrrolo-pyridone derivatives as potent Cbl-b inhibitors. Using structure-based drug design, we identified key structural elements that enhance binding affinity and inhibitory potency. Notably, compound B2 stands out, showing superior potency in stimulating IL-2 production in T cells and modulating phosphorylation of key proteins in T-cell receptor signaling. Furthermore, B2 demonstrates favorable pharmacokinetics and significantly inhibits tumor growth in vivo, outperforming NX-1607, which is currently in clinical trials.

2024-04-02·Expert opinion on therapeutic targets

Current strategies for targeting HPK1 in cancer and the barriers to preclinical progress

Review

作者: He, Chi ; Chen, Hui ; Guan, Xiangna ; Lin, Xingyu ; Liao, Xuebin ; Lu, Tingting

INTRODUCTION:

Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, functions as an intracellular negative regulator, primarily in hematopoietic lineage cells, where it regulates T cells, B cells, dendritic cells, and other immune cells. Loss of HPK1 kinase activity results in exacerbated cytokine secretion, enhanced T cell signaling, improved viral clearance, and thus increased restraint of tumor growth. These findings highlight HPK1 as a promising target for immuno-oncology treatments, culminating in the advancement of candidate compounds targeting HPK1 to clinical trials by several biotech enterprises.

AREAS COVERED:

Through searching PubMed, Espacenet-patent search, and clinicaltrials.gov, this review provides a comprehensive analysis of HPK1, encompassing its structure and roles in various downstream signaling pathways, the consequences of constitutive activation of HPK1, and potential therapeutic strategies to treat HPK1-driven malignancies. Moreover, the review outlines the patents issued for small molecule inhibitors and clinical investigations of HPK1.

EXPERT OPINION:

To enhance the success of tumor immunotherapy in clinical trials, it is important to develop protein degraders, allosteric inhibitors, and antibody-drug conjugates based on the crystal structure of HPK1, and to explore combination therapy approaches. Although several challenges remain, the development of HPK1 inhibitors display promising in preclinical and clinical studies.

2023-05-01·Journal of neuro-oncology

A novel CDK4/6 inhibitor combined with irradiation demonstrates potent anti-tumor efficacy in diffuse midline glioma.

Article

作者: Zuo, Pengcheng ; Wu, Zhen ; Zhang, Junting ; Lin, Xingyu ; Wang, Tantan ; Liao, Xuebin ; Li, Yaopeng ; Zhang, Liwei

OBJECTIVE:

Diffuse midline glioma, H3 K27-altered (DMG) is a lethal pediatric brainstem tumor. Despite numerous efforts to improve survival benefits, its prognosis remains poor. This study aimed to design and synthesize a novel CDK4/6 inhibitor YF-PRJ8-1011, which exhibited more potent antitumor activity against a panel of patient-derived DMG tumor cells in vitro and in vivo compared with palbociclib.

METHODS:

Patient-derived DMG cells were used to assess the antitumor efficacy of YF-PRJ8-1011 in vitro. The liquid chromatography tandem-mass spectrometry method was used to measure the activity of YF-PRJ8-1011 passing through the blood-brain barrier. DMG patient-derived xenograft models were established to detect the antitumor efficacy of YF-PRJ8-1011.

RESULTS:

The results showed that YF-PRJ8-1011 could inhibit the growth of DMG cells both in vitro and in vivo. YF-PRJ8-1011 could well penetrate the blood-brain barrier. It also significantly inhibited the growth of DMG tumors and prolonged the overall survival of mice compared with vehicle or palbociclib. Most notably, it exerted potent antitumor efficacy in DMG in vitro and in vivo compared with palbociclib. In addition, we also found that YF-PRJ8-1011 combined with radiotherapy also showed more significant inhibition of DMG xenograft tumor growth than radiotherapy alone.

CONCLUSION:

Collectively, YF-PRJ8-1011 is a novel, safe, and selective CDK4/6 inhibitor for DMG treatment.

项与广州宇繁南图生物科技有限公司相关的新闻（医药）

2022-06-21

·生物制品圈

免疫治疗新星：靶向HPK1的药物研发进展

造血祖细胞激酶1（Hematopoietic progenitor kinase 1 ，HPK1）是T细胞受体、B细胞受体和树突状细胞的负调节因子。HPK1激酶功能的丧失增加了细胞因子的分泌，增强了T细胞信号传导、病毒清除和肿瘤生长抑制。因此，HPK1被认为是肿瘤免疫治疗的一个有希望的靶点。据报道，几种HPK1抑制剂可调节T细胞功能。此外，还开发了能够诱导HPK1降解的HPK1靶向蛋白。最新一期JMC上，尤启冬等综述了HPK1的蛋白结构、功能和抑制剂的研究现状，并对HPK1靶向药物的未来发展提出了展望。HPK1是hematopoietic progenitor kinase 1（造血祖细胞激酶1）的简称，又名MAP4K1，是MAP4K家族的成员之一，它是一种丝/苏氨酸蛋白激酶。MAP4K家族中除HPK1外还有5个成员，包括MAP3K2、MAP4K3、MAP4K4、MAP4K5和MAP4K6。HPK1蛋白结构由N端激酶结构域（HPK1-KD）、四个富含脯氨酸（PR）的基序（PR1、PR2、PR3、PR4）和C端的柠檬酸同源结构域组成。PR1、PR2和PR4含有典型的II类结合基序，可与一系列含有Src同源3（SH3）结构域的衔接蛋白结合，如Grb2、Gads、Crk I/II、CrkL、Nck和HIP-55。这种结合模式不诱导磷酸化，表明HPK1蛋白的支架作用。HPK1的C端同源结构域可能作为调节结构域参与分子间相互作用。全长HPK1可在半胱氨酸蛋白酶切割位点（DDVD）被Caspas3切割，从而提高HPK1-KD的催化活性。HPK1激酶HPK1可与许多接头蛋白结合，如SLP76家族，Gads、HIP-55、GRB2家族，LAT、CRK家族等相互作用，活化造血干细胞的SAPK/JNK信号途径，从而对TCR通路进行负向调节。HPK1激酶是TCR信号的关键负反馈调节因子，能负调控树突细胞活化和T细胞与B细胞反馈；而抑制HPK1可增强T细胞活性，从而提高抗肿瘤免疫。HPK1主要由造血细胞包括其祖细胞表达。在T-细胞中，HPK1通过磷酰化SLP76上的Ser376和Gads上的Thr254激活SLP76，其磷酸化的复合体参与ERK信号途径的下调，并接到SLP-76的泛素化降解过程，导致TCR信号通路和T细胞增殖下降。2018年，Genentech的研究人员在Cell report上发表了一篇论文，显示共同阻断HPK1和PD-L1增强了抗肿瘤反应，证实HPK1可能提高检查点抑制剂功效。2020年8月28日，清华大学药学院廖学斌课题组与中山大学魏来课题组合作在《Cancer Cell》杂志上发表文章“造血祖细胞激酶1 (HPK1)通过有效调控T细胞功能，成为T细胞免疫治疗的药物靶点（Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies）”，该工作进一步证实HPK1可成为T细胞免疫疗法的药物热门研发靶点。HPK1抑制剂十多年前，研发人员就发现了HPK1可能是一种潜在的癌症免疫治疗靶点，但截止目前尚还没有相关药物上市。HPK1抑制剂开发所面临的挑战主要是HPK1 家族成员功能不同，设计高选择性抑制性化合物难度较大。据不完全统计，处于临床研发阶段的HPK1抑制剂包括：CFI-402411：是Treadwell Therapeutics公司研发的一种口服强效HPK1激酶抑制剂。临床前研究表明CFI-402411有望作为一种潜在的单一疗法，并与多种实体和血液癌症模型中的现有检查点抑制剂结合使用。2020年9月2日，该公司宣布CFI-402411的1/2期研究将进行首次患者给药，以评估TWT-101在实体瘤患者中作为单一疗法或与PD-1抑制剂联用的疗效。BGB-15025：是百济神州开发的一款高强度、高选择性的HPK1小分子口服抑制剂。2021年3月10日，百济神州公司宣布，一项针对其在研造血干细胞激酶1（HPK1）抑制剂BGB-15025的1期临床试验已完成首例患者给药。PRJ1-3024：是珠海宇繁研发的HPK1小分子抑制剂。PRJ1-3024胶囊分别于2021年11月和2022年2月在美国和中国进入临床试验阶段，主要用于胰腺癌、结直肠癌、肝癌等恶性肿瘤的免疫治疗。NDI-101150：无公开信息。其他研发中的小分子抑制剂结构包括下图（全部结构请阅读原文）等：已经报道的HPK1降解剂包括：在过去的5年中，已经报道了大量针对HPK1的小分子激酶抑制剂，大多数是ATP竞争性抑制剂。综合结构信息，作者发现与铰链相连的常见支架结构多为吲哚唑、氨基吡啶、氮杂吲哚等；面对P环的基团通常基于取代苯基或吡啶环；溶剂区域倾向于引入增溶基团如哌嗪或含氮杂环等。开发HPK1抑制剂的主要挑战是难以在MAP4K激酶家族中获得足够的选择性。此外，很难避免抑制参与TCR信号传导的其他相关激酶，如Src和其他Ste20样激酶家族。此外。已经报道了几种基于PROTAC技术的HPK1降解剂，这为靶向HPK1治疗创造了一个新的窗口，并可能进一步增强激酶的选择性。识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

免疫疗法小分子药物细胞疗法抗体蛋白降解靶向嵌合体

100 项与广州宇繁南图生物科技有限公司相关的药物交易

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药物(靶点)	适应症	全球最高研发状态

PRJ1-3024 ( HPK1 )	局部晚期恶性实体瘤更多	临床1/2期
YF-PRJ8-1011 ( CDK4 x CDK6 )	胶质瘤更多	临床前
YF550-C1 ( Cbl-b )	非小细胞肺癌更多	临床前
WO2024153240 ( Cbl-b )专利挖掘	神经系统疾病更多	药物发现
CN119630654 ( GSPT1 )专利挖掘	神经系统疾病更多	药物发现