title: Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond.
abstract: Chronic lymphocytic leukemia (CLL) remains the most incurable leukemia. Early chemotherapeutic treatments, including alkylating agents, purine nucleoside derivatives, and immunotherapeutic antibodies, only show limited benefits for patients but severe off-target related side effects. Recent advances in understanding of the critical molecular pathways of regulating proliferation and survival of B-CLL cells have spurred a new therapeutical strategy by selectively targeting phosphoinositide 3-kinase delta (PI3Kδ). Idelalisib, a first-in-class PI3Kδ-selective small molecule has received the FDA's fast-track approval in July of 2014 as a new treatment of CLL, indolent B-cell non-Hodgkin's lymphoma, and relapsed small lymphocytic lymphoma. Undoubtedly, the success of idelalisib has provided a solid support in the development of PI3Kδ-specific inhibitors and reformed the concept of treating CLL. However, the number of reported selective inhibitors of PI3Kδ is very limited and very few have advanced into clinical trials. The mechanism of their actions remains elusive. More profound understanding on the modes of action of new PI3Kδ inhibitors will further validate the PI3Kδ-targeting strategy, and help to identify biomarkers capable of stratifying patients who will most likely benefit from the therapy.
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Manman
authors.initials: M
authors.lastname: Wei
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Zilan
authors.initials: Z
authors.lastname: Song
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Mingkun
authors.initials: M
authors.lastname: Jiao
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Meng
authors.affiliation: CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011947:Receptors, Antigen, B-Cell
keywords: PI3Kδ; chronic lymphocytic leukemia; idelalisib; inhibitor; molecularly targeted therapy