Therapeutic Targeting a Non-Hodgkin Lymphoma Driver Using AI

使用人工智能针对非霍奇金淋巴瘤驱动者进行治疗

基本信息

批准号：
10585717
负责人：
Yong Li
金额：
$ 65.61万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-16 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585717
关键词：
Abnormal Cell Adaptor Signaling Protein Address Adoption Affect Agammaglobulinaemia tyrosine kinase Age Amino Acid Substitution Artificial Intelligence Artificial Intelligence platform Attenuated B-Cell Activation B-Cell NonHodgkins Lymphoma B-Lymphocytes Binding Sites Biochemical Reaction Biological Assay Blood typing procedure Body part Cancer Biology Cell Survival Cells Cessation of life Classification Clinical Clinical Trials Collaborations Cultured Cells Data Drug Kinetics Extranodal Genes Growth Hematopoietic Neoplasms Hodgkin Disease Immune response Immune system Immunity In Vitro In complete remission Indolent Industrialization Inflammation Innate Immune Response Investigational Drugs Knowledge Leucine Link Lymphocyte Lymphoma Lymphoma cell Lysine Malignant Neoplasms Mediating Medicine Missense Mutation Mutate Mutation Myelogenous Natural Immunity Non-Hodgkin&apos s Lymphoma Nuclear Oncogenes Oncogenic Oncoproteins Outcome Pathogenesis Patients Phosphotransferases Physiological Polyubiquitin Positioning Attribute Proline Proteins Publishing Reed-Sternberg Cells Ring Finger Domain Signal Transduction Site Solid Structure Technology Testing Therapeutic Agents Toll-like receptors Toxic effect Transgenic Organisms Ubiquitination United States Waldenstrom Macroglobulinemia Work Xenograft procedure adaptive immune response adaptive immunity cancer therapy causal variant college deep learning drug candidate drug development drug discovery in vivo inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma mouse model multicatalytic endopeptidase complex neural network novel therapeutics precision medicine protein degradation response screening small molecule success therapeutic development therapeutic target tumorigenesis virtual

项目摘要

Therapeutic Targeting a Non-Hodgkin Lymphoma Driver using AI PROJECT SUMMARY Baylor College of Medicine (BCM) and Atomwise Incorporation have partnered to discover, optimize, and test inhibitors to undruggable oncoproteins using artificial intelligence (AI). Both Hodgkin lymphoma and non- Hodgkin lymphoma (NHL) are cancers that start in lymphocytes, which are part of the body’s immune system. The main difference between Hodgkin lymphoma and NHL is in the specific lymphocyte each involves: in the presence of abnormal cells called Reed-Sternberg cells, the lymphoma is classified as Hodgkin’s; otherwise, it is classified as NHL. NHL is the most common blood cancer and causes over 20,000 deaths every year in the United States. There are about 90 types of NHL, which usually develop when mutations occur within a lymphocyte. The gene MYD88 encodes myeloid differentiation primary response 88 protein, a critical universal adapter with essential functions in inflammation and immunity. Following stimulation of toll-like receptors, MYD88 transduces the signal to activate genes responsible for innate and adaptive immune responses. MYD88 is a driver oncogene that is frequently mutated in B-cell NHLs. The most frequent missense mutation is L265P, which changes leucine at position 265 to proline and accounts for ~90% of all MYD88 mutations. MYD88 L265P is found in ~90% of Waldenström macroglobulinemia (WM, a rare NHL), >50% of primary extranodal lymphomas, and ~29% of activated B-cell diffuse large B-cell lymphomas (DLBCL). WM is considered incurable. DLBCL can be cured in about 40% of the patients, but those with MYD88 L265P have poorer survival than those without. BCM collaborates with Atomwise, the inventor of the first deep learning AI technology based on neural networks and a leader in AI-assisted drug discovery, to virtually screen 2.7 million compounds. We identified scores of AI-selected compounds targeting a binding site near L265P in MYD88. We validated these hits by evaluating their inhibition of MYD88 L265P ubiquitination and xenograft tumorigenesis. One compound attenuated lymphoma growth from NHL cells with MYD88 L265P, but not that with WT MYD88. We hypothesize that adaptor oncoproteins such as MYD88 L265P can be targeted by AI. In this application, we propose two specific aims to develop drug candidates that target MYD88 L265P for NHL therapy. In Aim 1, we will use AI to virtually screen billions of compounds to discover novel drug candidates targeting a binding site near L265P in MYD88. In Aim 2, we will optimize validated hit compounds targeting MYD88 L265P. Data generated from this partnership will provide a solid scientific platform for therapeutic development targeting the oncogenic MYD88 L265P while sparing WT MYD88, which is critical for both innate and adaptive immunity. This work addresses the unmet clinical need to target MYD88 L265P directly and advances drug development against mutation-specific drivers.

使用人工智能针对非霍奇金淋巴瘤驱动因素进行治疗项目概要贝勒医学院 (BCM) 和 Atomwise Incorporation 合作发现、优化和测试使用人工智能（AI）抑制不可成药的癌蛋白，包括霍奇金淋巴瘤和非霍奇金淋巴瘤。霍奇金淋巴瘤 (NHL) 是一种始于淋巴细胞的癌症，淋巴细胞是人体免疫系统的一部分。霍奇金淋巴瘤和 NHL 之间的主要区别在于各自涉及的特定淋巴细胞：存在称为里德-斯滕伯格细胞的异常细胞，则淋巴瘤被归类为霍奇金淋巴瘤；否则， NHL 是最常见的血癌，每年导致 20,000 多人死亡。美国大约有 90 种类型的 NHL，通常在基因突变时发生。基因 MYD88 编码骨髓分化初级反应 88 蛋白，这是一种关键的通用蛋白。在刺激 Toll 样受体后，具有炎症和免疫重要功能的接头， MYD88 转导信号以激活负责先天性和适应性免疫反应的基因。 MYD88 是 B 细胞 NHL 中经常发生突变的驱动癌基因，也是最常见的错义基因。突变为 L265P，将 265 位亮氨酸变为脯氨酸，约占所有 MYD88 的 90% MYD88 L265P 突变存在于 ~90% 的华氏巨球蛋白血症（WM，一种罕见的 NHL）中，>50% 的病例中发现了突变。原发性结外淋巴瘤，约 29% 的活化 B 细胞弥漫性大 B 细胞淋巴瘤 (DLBCL)。大约 40% 的 DLBCL 被认为是无法治愈的，但患有 MYD88 L265P 的患者则可以治愈。 BCM 与第一个深度学习 AI 的发明者 Atomwise 合作，生存率较差。基于神经网络的技术和人工智能辅助药物发现领域的领导者，可对 270 万人进行虚拟筛查我们鉴定了数十种针对 MYD88 中 L265P 附近结合位点的 AI 选择化合物。通过评估它们对 MYD88 L265P 泛素化和异种移植肿瘤发生的抑制作用，验证了这些命中。一种化合物可以减弱 MYD88 L265P 的 NHL 细胞的淋巴瘤生长，但不能减弱 WT MYD88 的淋巴瘤生长。我们希望 AI 能靶向诸如 MYD88 L265P 之类的接头癌蛋白。申请中，我们提出了两个具体目标来开发针对 NHL 的 MYD88 L265P 候选药物在目标 1 中，我们将使用人工智能虚拟筛选数十亿种化合物，以发现新的候选药物。目标 MYD88 中 L265P 附近的结合位点在目标 2 中，我们将优化经过验证的命中目标化合物。此次合作产生的 MYD88 L265P 数据将为治疗提供坚实的科学平台。针对致癌 MYD88 L265P 的开发，同时保留 WT MYD88，这对于先天性和遗传性都至关重要这项工作解决了直接靶向 MYD88 L265P 的未满足的临床需求。推进针对突变特异性驱动因素的药物开发。