生物活性

• 靶点

  p110α IC50:820nM

  p110β IC50:565nM

  p110γ IC50:89nM

  p110δ IC50:2.5nM

• 描述PI3Ks are lipid kinases participating in several cellular process. There are eight PI3Ks, which have been identified as classes IA, 1B, II and III based on the sequence homology and substrate preference. The class IA PI3K is a heterodimer consisting of a 110 kDa catalytic subunit (p110α, p110β and p110δ), and an 85 kDa regulatory subunit^[2]. CAL-101 is an orally available and selective inhibitor of p110δ (IC50=2.5nM, analyzed using the SelectScreen kinase inhibitor assay service) with less potent to p110γ (IC50=89nM). In SU-DHL-5, KARPAS-422 and B-ALL (CCRF-SB) cell lines, CAL-101 can produce a concentration-dependent reduction in pAktS473, pAktT308 and the downstream target S6 and also induce apoptosis significantly^[1]. It has also been found that CAL-101 can induce caspase-dependent death of malignant CLL cells, suppresse the production of protumor cytokine by T and NK cells, as well as abrogate prosurvival microenvironmental signals like B-cell activating factor, tumor necrosis factor and fibronectin^[3]. Thus, CAL-101 has effects both on tumor microenvironment and directly on tumors. Now CAL-101 has been used in monotherapy studies in patients with non-Hodgkin lymphoma (Phase1/2)^[4].
• 作用机制Idelalisib can bind to the ATP-binding pocket of PI3Kδ, which is responsible for the selectivity for PI3Kδ.^[5]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  CCRF-SB	1 μM	Function Assay	24 h	Induction of apoptosis	20959606
  CLL PBMCs	-	Growth Inhibition Assay	-	IC50=2.9 nM	25917267
  DERL7	10 μM	Growth Inhibition Assay	72 h	does not induce apoptosis	22801959

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• 动物研究
  剂量	Mice: min = 10 mg/kg[6], max = 40 mg/kg[7]
  给药途径	p.o, i.v, i.p

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03310190	-	-	Recruiting	June 15, 2020	Canada, Alberta ... more >> University of Calgary /ID# 166416 Recruiting Calgary, Alberta, Canada, T2N 4Z6 Cross Cancer Institute /ID# 166417 Not yet recruiting Edmonton, Alberta, Canada, T6G 1Z2 Canada, New Brunswick The Moncton Hospital /ID# 166043 Recruiting Moncton, New Brunswick, Canada, E1C 6Z8 Saint John Regional Hospital /ID# 202190 Not yet recruiting Saint John, New Brunswick, Canada, E2L 4L2 Canada, Ontario William Osler Health System /ID# 202049 Not yet recruiting Brampton, Ontario, Canada, L6R 3J7 Michael Garron Hospital/Toronto East Health Network /ID# 209463 Not yet recruiting East York, Ontario, Canada, M4C 3E7 Kingston Health Sciences Centr /ID# 169252 Recruiting Kingston, Ontario, Canada, K7L 2V7 The Ottawa Hospital Research /ID# 166041 Recruiting Ottawa, Ontario, Canada, K1H 8L6 Health Sciences North /ID# 205817 Recruiting Sudbury, Ontario, Canada, P3N 1H5 Canada, Quebec Jewish General Hospital /ID# 166418 Recruiting Montreal, Quebec, Canada, H3T 1E2 Cisss Du Bas-Saint-Laurent Hopital Regional de Rimouski /Id# 201202 Recruiting Rimouski, Quebec, Canada, G5L 5T1 Canada CancerCare Manitoba /ID# 170751 Recruiting Manitoba, Canada, R3E 0V9 Thunder Bay Regional Health Re /ID# 204740 Not yet recruiting Thunder Bay, Canada, P7B 6V4 Collapse <<
  NCT03283137	CLL B-cell No... more >>n Hodgkin Lymphoma Collapse <<	Phase 1	Recruiting	December 2020	United States, Illinois ... more >> University of Chicago Recruiting Chicago, Illinois, United States, 60637 Contact: Michael Thirman, MD       mthirman@medicine.bsd.uchicago.edu    Contact: Howard Weiner    7737022084    hweiner@medicine.bsd.uchicago.edu Collapse <<
  NCT02141282	Chronic Lymphocytic Leukemia	Phase 2	Active, not recruiting	December 8, 2021	United States, California ... more >> Ucsd /Id# 128535 La Jolla, California, United States, 92037 University of California, Los Angeles /ID# 127262 Los Angeles, California, United States, 90095 Stanford Univ School of Med /ID# 126495 Stanford, California, United States, 94305-2200 United States, District of Columbia Medstar Georgetown Univ Med Ct /ID# 127261 Washington, District of Columbia, United States, 20007 United States, Georgia Emory University Hospital /ID# 131249 Atlanta, Georgia, United States, 30322 United States, Illinois Northwestern University /ID# 126497 Chicago, Illinois, United States, 60611-2927 United States, Massachusetts Beth Israel Deaconess Med Ctr /ID# 134509 Boston, Massachusetts, United States, 02215-5400 Dana-Farber Cancer Institute /ID# 126496 Boston, Massachusetts, United States, 02215 United States, Minnesota Mayo Clinic - Rochester /ID# 130013 Rochester, Minnesota, United States, 55905-0001 United States, New York Columbia Univ Medical Center /ID# 128536 New York, New York, United States, 10032-3725 New York Presbyterian Hospital - Weill Cornell Medical Center /ID# 129648 New York, New York, United States, 10032-3725 Univ Rochester Med Ctr /ID# 130011 Rochester, New York, United States, 14642 United States, Ohio The Ohio State University - Columbus /ID# 127263 Columbus, Ohio, United States, 43210 United States, Pennsylvania University of Pennsylvania /ID# 126860 Philadelphia, Pennsylvania, United States, 19104-5502 United States, Texas Univ TX, MD Anderson /ID# 126498 Houston, Texas, United States, 77030 United States, Utah University of Utah /ID# 129984 Salt Lake City, Utah, United States, 84112-5500 University of Utah /ID# 130813 Salt Lake City, Utah, United States, 84112-5500 Collapse <<

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• 参考文献

• [1] Lannutti BJ, Meadows SA, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011 Jan 13;117(2):591-4.

  [2] Zhao HF, Wang J, et al. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Mol Cancer. 2017 Jun 7;16(1):100.

  [3] Herman SE, Gordon AL, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010 Sep 23;116(12):2078-88.

  [4] Cheah CY, Fowler NH, et al. Idelalisib in the management of lymphoma. Blood. 2016 Jul 21;128(3):331-6.

  [5] Berndt A, Miller S, et al. The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat Chem Biol. 2010 Feb;6(2):117-24.

  [6] Ahmad S, Abu-Eid R, et al. Differential PI3Kδ Signaling in CD4⁺ T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy. Cancer Res. 2017;77(8):1892-1904.

  [7] Low PC, Manzanero S, et al. PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model. Nat Commun. 2014.

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