Norman Consulting, Burnham, UK.
Expert Opin Ther Pat. 2011 Nov;21(11):1773-90. doi: 10.1517/13543776.2011.629606.
Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is the first kinase involved in, and a key component of, the PI3K/Akt/mTOR signalling pathway, and is significantly upregulated in many cancers. However, four distinct isoforms of PI3K are known with different expression patterns and different pathophysiological roles. The PI3Kδ isoform is expressed in leukocytes and has been implicated as a potential target in the development of selective inhibitors for the treatment of haematological malignancies and various inflammatory diseases.
This review briefly covers the understanding of the four PI3K isoforms and their roles and the inhibitors selective for either one or two isoforms that have been identified to date. It then focuses upon progress in the identification of selective PI3Kδ inhibitors focusing upon the original efforts at ICOS/Calistoga that led to the initial clinical candidates such as CAL-101. After assessing the patent filings from these companies, it considers filings from other players and how they have sought to explore similar, and structurally distinct, scaffolds in their search for selective inhibitors, and how different companies appear focused on either oncological or anti-inflammatory uses for their inhibitors.
The impact of the work at ICOS is highlighted by the fact that prior to their disclosure of selective leads, no patent applications claiming selective PI3Kδ inhibitors had been filed by other companies. This disclosure, followed by the first filings by Piramed, led to an upsurge in interest with a large cluster of filings published in 2008 while half the relevant applications were published in 2010 or 2011. These efforts, and the initial clinical data on CAL-101, the leading PI3Kδ inhibitors, have also prompted a number of commercially significant deals. In addition to an increasing number of filings, the entry into the clinical development of more selective PI3Kδ inhibitors should stimulate a better understanding of the role of this specific kinase isoform.
磷脂酰肌醇 3-激酶（PI3K）是一种脂质激酶，是参与 PI3K/Akt/mTOR 信号通路的第一个激酶，也是许多癌症中显著上调的关键组成部分。然而，已知有四种不同的 PI3K 同工型，它们具有不同的表达模式和不同的病理生理作用。PI3Kδ 同工型在白细胞中表达，并被认为是开发选择性抑制剂治疗血液恶性肿瘤和各种炎症性疾病的潜在靶点。
本文简要概述了对四种 PI3K 同工型及其作用的理解，以及迄今为止已鉴定出的针对一种或两种同工型的选择性抑制剂。然后，本文重点介绍了 PI3Kδ 选择性抑制剂的鉴定进展，重点介绍了最初在 ICOS/Calistoga 所做的努力，这些努力导致了最初的临床候选药物，如 CAL-101。在评估这些公司的专利申请后，本文考虑了其他参与者的专利申请，以及它们如何在寻找选择性抑制剂时探索相似的、结构不同的支架，以及不同的公司似乎专注于其抑制剂的肿瘤学或抗炎用途。
ICOS 工作的影响体现在一个事实，即在其他公司提出选择性 PI3Kδ 抑制剂的专利申请之前，没有任何公司提出过这样的专利申请。这一披露，以及 Piramed 的首次申请，引发了人们的浓厚兴趣，2008 年公布了一大批申请，而 2010 年或 2011 年公布了一半相关申请。这些努力以及 CAL-101 的初步临床数据，也促使了一些具有商业意义的交易。除了越来越多的专利申请外，更多选择性 PI3Kδ 抑制剂进入临床开发阶段，也应该会促进对这一特定激酶同工型作用的更好理解。
