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CAL-101 (Idelalisib, GS-1101)

PI3K inhibitor CAS# 870281-82-6

CAL-101 (Idelalisib, GS-1101)

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Chemical structure

CAL-101 (Idelalisib, GS-1101)

3D structure

Chemical Properties of CAL-101 (Idelalisib, GS-1101)

Cas No. 870281-82-6 SDF Download SDF
PubChem ID 11625818 Appearance Powder
Formula C22H18FN7O M.Wt 415.43
Type of Compound N/A Storage Desiccate at -20°C
Synonyms GS-1101; Idelalisib
Solubility DMSO : ≥ 59.7 mg/mL (143.71 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4-one
SMILES CCC(C1=NC2=C(C(=CC=C2)F)C(=O)N1C3=CC=CC=C3)NC4=NC=NC5=C4NC=N5
Standard InChIKey IFSDAJWBUCMOAH-HNNXBMFYSA-N
Standard InChI InChI=1S/C22H18FN7O/c1-2-15(28-20-18-19(25-11-24-18)26-12-27-20)21-29-16-10-6-9-14(23)17(16)22(31)30(21)13-7-4-3-5-8-13/h3-12,15H,2H2,1H3,(H2,24,25,26,27,28)/t15-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of CAL-101 (Idelalisib, GS-1101)

DescriptionCAL-101 (Idelalisib, GS-1101) is a selective inhibitor of p110δ with IC50 of 2.5 nM.
Targetsp110δ    
IC502.5 nM     

Protocol

Cell experiment: [1]

Cell lines

CD19/CD5-positive CLL cells (> 90%)

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

< 5 μM: dose-dependently inhibits the pro-survival effect of anti-IgM = 5 μM, 24h: inhibits 2.6% activity of anti-IgM > 5 μM, 72h: maximally reduces CLL cell viability

Applications

CAL-101 abrogated the pro-survival effect of anti-IgM in a dose-dependent fashion at lower dose levels (< 5 μM). CAL-101 treatment at concentrations of > 5 μM was maximally effective over the 72-hour time course in reducing CLL cell viability. At the 5 μM concentration, CAL-101 significantly decreased the mean ( SEM) pro-survival effect of anti-IgM to 92.7% ( 2.6%) after 24 hours.

Animal experiment : [2]

Animal models

NOD-SCID-γ-null (NSG) mice well-engrafted with de novo (n = 3) or relapsed (n = 1) childhood Ph-like ALL specimens with JAK2 mutations and/or CRLF2 alterations.

Dosage form

30 mg/kg/day, 3 days, oral gavage

Application

CAL101 treatments demonstrated potent in vivo inhibition of relevant phosphoproteins, including phosphorylated (p) PI3K, mTOR, S6, and AktS473. Increased phosphorylation of other measured proteins was not observed, suggesting that proximal inhibition effectively abrogated aberrant PI3K pathway signal transduction with minimal compensatory signaling upregulation.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Hoellenriegel J, Meadows S A, Sivina M, et al. The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood, 2011, 118(13): 3603-3612.

[2] Li Y, Ryan T, Vincent T, et al. In vivo efficacy of PI3K pathway signaling inhibition for Philadelphia chromosome-like acute lymphoblastic leukemia. Blood, 2013, 122(21): 2672-2672.

CAL-101 (Idelalisib, GS-1101) Dilution Calculator

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Preparing Stock Solutions of CAL-101 (Idelalisib, GS-1101)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.4071 mL 12.0357 mL 24.0714 mL 48.1429 mL 60.1786 mL
5 mM 0.4814 mL 2.4071 mL 4.8143 mL 9.6286 mL 12.0357 mL
10 mM 0.2407 mL 1.2036 mL 2.4071 mL 4.8143 mL 6.0179 mL
50 mM 0.0481 mL 0.2407 mL 0.4814 mL 0.9629 mL 1.2036 mL
100 mM 0.0241 mL 0.1204 mL 0.2407 mL 0.4814 mL 0.6018 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of CAL-101 (Idelalisib, GS-1101)

2. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011 Sep 29;118(13):3603-12. doi: 10.1182/blood-2011-05-352492. Epub 2011 Jul 29.
Abstract
CAL-101 is a selective inhibitor of PI3Kδ that induces rapid lymph node shrinkage and a transient lymphocytosis in CLL cells. CAL-101 not only directly inhibits the pro-survival PI3K pathway but also disrupts CLL-microenvironment interactions, where it inhibits chemotaxis and migration of CLL cell, down-regulates BCR-induced chemokines secretion, reduces survival signals and suppresses ERK activation.
3. PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood. 2012 Feb 23;119(8):1897-900. doi: 10.1182/blood-2011-10-386763. Epub 2011 Dec 30.
Abstract
CAL-101, an oral inhibitor of PI3Kδ, inhibited AKT phosphorylation and stroma-induced Akt activation, reduced CCL5 production and dose-dependently induced apoptosis in HL cells. Moreover, addition of everolimu could enhance the anti-HL activity of CAL-101.
4. 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. doi: 10.1182/blood-2010-03-275305. Epub 2010 Oct 19.
Abstract
CAL-101 is an inhibitor of p110δ that blocks phosphatidylinositol-3-kinase signaling in a wide range of B-cell malignancies leading to decreased phosphorylation of Akt and other downstream effectors, increased polu(ADP-ribose) polymerase and caspase cleavage and induced apoptosis.
5. Translating PI3K-Delta Inhibitors to the Clinic in Chronic Lymphocytic Leukemia: The Story of CAL-101 (GS1101). Am Soc Clin Oncol Educ Book. 2012;32:691-694. doi: 10.14694/EdBook_AM.2012.32.691.
Abstract
CAL-101, a p110 delta inhibitor, has been developed fr the treatment of chronic lymphoid malignancies including CLL.

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Background on CAL-101 (Idelalisib, GS-1101)

CAL-101 (Idelalisib, GS-1101), is a p110δ selective phosphatidylinositol-3-kinase inhibitor in a kinome-wide screen using purified enzymes and in cell-based PI3K isoform-specific assays. Phosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. CAL-101 can block constitutive phosphatidylinositol-3-kinase signaling, resulting in reduced phosphorylation of Akt and other downstream effect factors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies. In addition, CAL-101 abrogated protection from spontaneous apoptosis induced by B cell–activating factors CD40L, TNF-α, and fibronectin.

Reference

Brian J. Lannutti, Sarah A. Meadows, Sarah E. M. Herman, Adam Kashishian, Bart Steiner, Amy J. Johnson, John C. Byrd, Jeffrey W. Tyner, Marc M. Loriaux, Mike Deininger, Brian J. Druker, Kamal D. Puri, Roger G. Ulrich, and Neill A. Giese. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011; 117(2): 591 – 594.

Sarah E. M. Herman, Amber L. Gordon, Amy J. Wagner, Nyla A. Heerema, Weiqiang Zhao, Joseph M. Flynn, Jeffrey Jones, Leslie Andritsos, Kamal D. Puri, Brian J. Lannutti, Neill A. Giese, Xiaoli Zhang, Lai Wei, John C. Byrd,  Amy J. Johnson. 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; 116(12): 2078 – 88.

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References on CAL-101 (Idelalisib, GS-1101)

Chronic lymphocytic leukemia: biology, disease progression, and current treatment strategies.[Pubmed:28978838]

Rinsho Ketsueki. 2017;58(10):1960-1972.

Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations. Current treatment approaches are not curative for CLL, except allogeneic hematopoietic stem cell transplantation, which is rarely offered to the majority of patients aged 70 years and older. Currently, there is no evidence that the initiation of therapy for asymptomatic early-stage disease improves the overall survival, even for patients with high-risk disease. The identification that the B-cell receptor (BCR) signaling pathway is aberrantly and constitutively activated in CLL has recently led to the development of BCR signaling inhibitors, ibrutinib and idelalisib. In addition, a novel BCL-2 antagonist, venetoclax, appears promising when used alone or in combination with anti-CD20 antibodies. The advent of novel small-molecule inhibitors has revolutionized the treatment approaches for patients with CLL.

Efficacy of idelalisib as bridge to allogeneic stem cell transplant in relapsed follicular lymphoma: a case report.[Pubmed:28967090]

Tumori. 2017 Nov 15;103(Suppl. 1):e41-e43.

PURPOSE: A large number of new therapeutic agents have been studied for patients with relapsed/refractory follicular lymphoma (FL). Among new therapies, idelalisib, a novel PI3K inhibitor, shows promising results in the management of this disease. CASE REPORT: We describe the case of a 39-year-old patient with a diagnosis of grade 3a FL and a Follicular Lymphoma International Prognostic Index score of 2, who underwent several lines of therapy (including autologous stem cell transplant) with transient responses or no response at all. The patient was subsequently treated with 5 courses of idelalisib monotherapy, achieving a partial response. No relevant toxicities occurred. The patient underwent allogeneic stem cell transplant (allo-SCT) from an unrelated donor and obtained a complete response, which was confirmed after 3, 6, 9, and 12 months, and is still ongoing. CONCLUSIONS: As previously reported, the achievement of a good response is predictive for a better outcome after allo-SCT: idelalisib represents an effective treatment option for patients with relapsed/refractory FL, which can also be adopted as a bridge to allo-SCT.

PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma.[Pubmed:28945111]

Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279.

INTRODUCTION: The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110delta in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kalpha and PI3Kdelta. Expert Opinion: PI3K inhibitors, particularly those that target p110delta, have robust efficacy in the treatment of CLL and iNHL. However, idelalisib has infectious and autoimmune toxicities that limit its use. Outside of trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia.[Pubmed:28942659]

Expert Opin Investig Drugs. 2017 Nov;26(11):1249-1265.

INTRODUCTION: Over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed. Publications from 2000 through July 2017 were scrutinized. The search terms used were acalabrutinib, ACP-196, BGB-3111, ONO-4059, GS-4059, duvelisib, IPI-145, TGR-1202, copanlisib, Bay 80-6946, buparlisib, BKM-120, BCL-2 inhibitors, venetoclax, ABT-263, navitoclax, CDK inhibitors, alvocidib, flavopiridol, dinaciclib, SCH 727,965, palbociclib, PD-0332991, in conjunction with CLL. Conference proceedings from the previous five years of the ASH and EHA Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: The use of new synthetic drugs is a promising strategy for the treatment of CLL. Data from ongoing and future clinical trials will aid in better defining the status of new drugs in the treatment of CLL.

Idelalisib plus rituximab is effective in systemic AL amyloidosis secondary to chronic lymphocytic leukaemia.[Pubmed:28971495]

Hematol Oncol. 2018 Feb;36(1):366-369.

Light chain amyloidosis is characterized by the progressive deposition of immunoglobulin light chains into the extracellular tissue, leading to organ dysfunction. Usually, it is associated with an underlying clonal plasma cell dyscrasia and rarely with chronic lymphocytic leukaemia. Herein, we described the first report of a patient with relapsed chronic lymphocytic leukaemia harbouring TP53 abnormalities who developed, histologically proven, systemic light chain amyloidosis who was treated with the PI3K inhibitor, idelalisib, and rituximab. Unfortunately, the patient had sudden death during sleep, likely caused by arrhythmia secondary to amyloid cardiomyopathy. Idelalisib was at least effective in reducing secretory free light chain, chronic lymphocytic leukaemia burden, and to improve the survival of patient.

Description

Idelalisib (CAL-101; GS-1101) is a highly selective and orally bioavailable p110δ inhibitor with an IC50 of 2.5 nM, showing 40- to 300-fold selectivity for p110δ over other PI3K class I enzymes.

Keywords:

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