Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies.

IF 8.2 1区 医学 Q1 HEMATOLOGY
Binu Kandathilparambil Sasi,Chiara Tarantelli,Stephen Martindale,Elisa Civanelli,Eleonora Cannas,Giulio Sartori,Alberto J Arribas,Stacey M Fernandes,Samantha J Shupe,John-Hanson Machado,Svitlana Tyekucheva,Yue Ren,Michael Lahn,Lars Van der Veen,Giusy Di Conza,Francesco Bertoni,Jennifer R Brown
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引用次数: 0

Abstract

The phosphoinositide 3-kinase (PI3K) pathway remains a potent drug target in hematological malignancies despite the challenges that have affected clinical drug development, particularly unpredictable toxicity, and inherent/acquired drug resistance. Herein, we tested the activity of a novel PI3Kδ selective, non-ATP competitive inhibitor, roginolisib (IOA-244), in hematological malignancies including diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). To identify rational actionable combination partners that can be tested in hematologic malignancies, an unbiased pharmacological screening of 474 compounds was carried out in two lymphoma cell lines. We identified BCL2 blockade with venetoclax as synergistically active with roginolisib, a finding confirmed in a broad panel of lymphoma cell lines, DLBCL cell lines and primary CLL samples. We further demonstrate that the sensitizing effects of roginolisib to venetoclax correlate with suppression of downstream PI3K/AKT pathways and alterations in the expression of the apoptotic proteins BIM, mediated through FOXO1 transactivation, and MCL1, with ubiquitination and degradation mediated through GSK3α/β activation. These findings support proof of concept for roginolisib development in hematological malignancies as a single agent or in combination with venetoclax. A clinical trial of roginolisib with venetoclax and an anti-CD20 antibody is initiating in CLL.
新型PI3kδ抑制剂roginolisib与venetoclax协同治疗血液恶性肿瘤
磷酸肌肽3-激酶(PI3K)途径仍然是血液系统恶性肿瘤的有效药物靶点,尽管存在影响临床药物开发的挑战,特别是不可预测的毒性和固有/获得性耐药。在此,我们测试了一种新的PI3Kδ选择性、非atp竞争性抑制剂roginolisib (IOA-244)在血液系统恶性肿瘤中的活性,包括弥漫性大B细胞淋巴瘤(DLBCL)和慢性淋巴细胞白血病(CLL)。为了确定可在血液恶性肿瘤中测试的合理可行的联合伙伴,在两个淋巴瘤细胞系中进行了474种化合物的无偏药理学筛选。我们发现venetoclax阻断BCL2与roginolisib具有协同活性,这一发现在广泛的淋巴瘤细胞系、DLBCL细胞系和原发性CLL样本中得到证实。我们进一步证明,roginolisib对venetoclax的增敏作用与下游PI3K/AKT通路的抑制和凋亡蛋白BIM表达的改变有关,通过FOXO1转激活介导,MCL1介导,通过GSK3α/β激活介导泛素化和降解。这些发现支持roginolisib作为单一药物或与venetoclax联合治疗血液系统恶性肿瘤的概念证明。一项roginolisib联合venetoclax和抗cd20抗体治疗CLL的临床试验正在启动。
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来源期刊
Haematologica
Haematologica 医学-血液学
CiteScore
14.10
自引率
2.00%
发文量
349
审稿时长
3-6 weeks
期刊介绍: Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research. Scope: The scope of the journal includes reporting novel research results that: Have a significant impact on understanding normal hematology or the development of hematological diseases. Are likely to bring important changes to the diagnosis or treatment of hematological diseases.
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