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CAL-101 (Idelalisib) PI3Kδ remmer

Name: CAL-101 (Idelalisib)
Brand: Selleck Chemicals
SKU: S2226
Rating: 5 (288 reviews)

Cat.Nr.S2226

Idelalisib (CAL-101) is een selectieve p110δ remmer met een IC50 van 2,5 nM in celvrije assays; getoond om 40- tot 300-voudig grotere selectiviteit te hebben voor p110δ dan p110α/β/γ, en 400- tot 4000-voudig meer selectiviteit voor p110δ dan C2β, hVPS34, DNA-PK en mTOR. Idelalisib stimuleert ook Autophagy.

CAL-101 (Idelalisib) PI3K Remmer Chemical Structure

Chemische structuur

Moleculair gewicht: 415.42

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Kwaliteitscontrole (Quality Control)

Batch: Zuiverheid: 99.93%

99.93

Gerelateerde doelwitten	Akt mTOR GSK-3 ATM/ATR DNA-PK AMPK PDPK1 PTEN PP2A PDK
Overige PI3K Inhibitoren	GDC-0077 (Inavolisib) SAR405 Quercetin (Sophoretin) LY294002 XL147 analogue Tersolisib (STX-478) Buparlisib (BKM120) 740 Y-P (PDGFR 740Y-P) GO-203 TFA Eganelisib (IPI-549)

Celkweek, behandeling & werkconcentratie
(Cell Culture, Treatment & Working Concentration)

Cellijnen	Assaytype	Concentratie	Incubatietijd	Formulering	Activiteitsbeschrijving	PMID
MEC1	Growth Inhibition Assay			DMSO	IC50=20.4 μM	25999352
CLL PBMCs	Growth Inhibition Assay			DMSO	IC50=2.9 nM	25917267
U266	Growth Inhibition Assay	40 μM	48 h		79.5% inhibition rate	25339332
K562	Function Assay	1 μM	3 h		Inhibition of Akt phosphorylation	25014775
K562	Function Assay	1 μM	3 h		Inhibition of P70S6K phosphorylation	25014775
K562	Function Assay	1 μM	3 h		Inhibition of GSK3 phosphorylation	25014775
K562	Growth Inhibition Assay	1 μM	72 h		Inhibition of proliferation	25014775
Primary AML cell	Function Assay	1 μM	3 h		Inhibition of Akt phosphorylation	25014775
Primary AML cell	Function Assay	1 μM	3 h		Inhibition of P70S6K phosphorylation	25014775
Primary AML cell	Function Assay	1 μM	3 h		Inhibition of GSK3 phosphorylation	25014775
Primary AML cell	Growth Inhibition Assay	1 μM	3 h		Suppression of rRNA synthesis	25014775
Microglia	Function Assay	5 μM	10 h	DMSO	Decrease of TNFa secretion from LPS-stimulated p110δD910A/D910A microglia	24625684
Primary CLL cell	Function Assay	1 μM	15 min	DMSO	Blocks BCR-induced LCP1 serine-5 activation	24009233
JEKO-1	Function Assay	1 μM	72 h		Inhibition of Akt phosphorylation in IgM-stimulated JEKO-1	23341541
Granta-519	Function Assay	1 μM	2 h		Inhibition of Akt(t308) phosphorylation	23341541
Granta-519	Function Assay	1 μM	2 h		Inhibition of Akt(s473) phosphorylation	23341541
JEKO-1	Growth Inhibition Assay	10 μM	72 h		Inhibition of proliferation slightly	23341541
JEKO-1	Growth Inhibition Assay	5 μM	72 h		does not induce cell cycle arrest or apoptosis	23676220
MAVER-1	Growth Inhibition Assay	5 μM	72 h		does not induce cell cycle arrest or apoptosis	23676220
MINO	Growth Inhibition Assay	5 μM	72 h		does not induce cell cycle arrest or apoptosis	23676220
SP53	Growth Inhibition Assay	0.1 μM	72 h		does not induce cell cycle arrest or apoptosis	23676220
HH	Growth Inhibition Assay	10 μM	72 h	DMSO	Induction of apoptosis slightly	22801959
Myla	Growth Inhibition Assay	10 μM	72 h	DMSO	does not induce apoptosis	22801959
SR786	Growth Inhibition Assay	10 μM	72 h	DMSO	does not induce apoptosis	22801959
HuT78	Growth Inhibition Assay	10 μM	72 h	DMSO	does not induce apoptosis	22801959
MJ	Growth Inhibition Assay	10 μM	72 h	DMSO	does not induce apoptosis	22801959
DERL7	Growth Inhibition Assay	10 μM	72 h	DMSO	does not induce apoptosis	22801959
L1236	Function Assay	10 μM	2 h		Inhibition of Akt phosphorylation	22210877
L428	Function Assay	10 μM	2 h		Inhibition of Akt phosphorylation	22210877
L591	Function Assay	10 μM	2 h		Inhibition of Akt phosphorylation	22210877
KMH-2	Function Assay	10 μM	2 h		Inhibition of Akt phosphorylation	22210877
L1236	Function Assay	5 μM	24 h		Blocks secretion of the CCL5	22210877
L591	Function Assay	5 μM	24 h		Blocks secretion of the CCL5	22210877
L1236	Apoptosis Assay	5 μM	24 h		Induction of apoptosis	22210877
L591	Apoptosis Assay	5 μM	24 h		Induction of apoptosis	22210877
U-87MG	Function Assay	100 nM	24 h	DMSO	Inhibition of cell migration	22079609
SW1783	Function Assay	100 nM	24 h	DMSO	Inhibition of cell migration	22079609
U-87MG	Function Assay	5 μM	24 h	DMSO	Inhibition of Akt phosphorylation substantially	22079609
SW1783	Function Assay	5 μM	24 h	DMSO	Inhibition of Akt phosphorylation substantially	22079609
U-373MG	Function Assay	5 μM	24 h	DMSO	Inhibition of Akt phosphorylation substantially	22079609
SK-MG3	Function Assay	5 μM	24 h	DMSO	Inhibition of Akt phosphorylation substantially	22079609
SU-DHL-5	Function Assay	1 μM	24 h	DMSO	Induction of apoptosis	20959606
WSU-NHL	Function Assay	1 μM	24 h	DMSO	Induction of apoptosis	20959606
CCRF-SB	Function Assay	1 μM	24 h	DMSO	Induction of apoptosis	20959606
INA-6	Function Assay	5 μM	6 h		Inhibition of PI3K/Akt and ERK pathway	20505158
LB	Function Assay	5 μM	6 h		Inhibition of PI4K/Akt and ERK pathway	20505158
B-cells	Function assay				Inhibition of PI3Kdelta in B-cells by proliferation assay, IC50 = 0.0061 μM.	22924688
MOLM14	Antiproliferative assay		3 days		Antiproliferative activity against human MOLM14 cells after 3 days by CellTiter-Glo assay, IC50 = 3.6 μM.	27774127
MV4-11	Antiproliferative assay		3 days		Antiproliferative activity against human MV4-11 cells after 3 days by CellTiter-Glo assay, IC50 = 6.3 μM.	27774127
Jurkat	Antiproliferative assay		3 days		Antiproliferative activity against human Jurkat cells after 3 days by CellTiter-Glo assay, IC50 = 7.9 μM.	27774127
Loucy	Antiproliferative assay		3 days		Antiproliferative activity against human Loucy cells after 3 days by CellTiter-Glo assay, IC50 = 8.4 μM.	27774127
MOLT4	Antiproliferative assay		3 days		Antiproliferative activity against human MOLT4 cells after 3 days by CellTiter-Glo assay, IC50 = 10.6 μM.	27774127
insect cells	Function assay				Inhibition of recombinant human full length His-tagged PI3Kgamma expressed in insect cells, IC50 = 0.089 μM.	27846451
SUDHL6	Antiproliferative assay		72 hrs		Antiproliferative activity against human SUDHL6 cells measured after 72 hrs by alamar blue assay, IC50 = 0.1176 μM.	27846451
insect cells	Function assay				Inhibition of recombinant human full length His-tagged PI3Kbeta expressed in insect cells, IC50 = 0.565 μM.	27846451
SU-DHL4	Antiproliferative assay		72 hrs		Antiproliferative activity against human SU-DHL4 cells measured after 72 hrs by alamar blue assay, IC50 = 1.6 μM.	27846451
Pfeiffer	Antiproliferative assay		72 hrs		Antiproliferative activity against human Pfeiffer cells measured after 72 hrs by alamar blue assay, IC50 = 6.8 μM.	27846451
KARPAS422	Antiproliferative assay		72 hrs		Antiproliferative activity against human KARPAS422 cells measured after 72 hrs by alamar blue assay, IC50 = 8.1 μM.	27846451
Sf21	Function assay		30 mins		Inhibition of N-terminal His6-tagged recombinant full-length human PI3K p110beta/untagged recombinant full length human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2/ATP as substrate after 30 mins by TR-FRET assay, IC50 = 3.7 μM.	28106991
Sf21	Function assay		30 mins		Inhibition of N-terminal His6-tagged recombinant full-length human PI3K p110beta/untagged recombinant full length human p85alpha expressed in baculovirus infected Sf21 insect cells using PIP2/ATP as substrate after 30 mins by TR-FRET assay, IC50 = 3.7 μM.	28106991
RPMI8266	Antiproliferative assay		72 hrs		Antiproliferative activity against human RPMI8266 cells after 72 hrs by MTT assay, IC50 = 0.00549 μM.	28325601
Raji	Antiproliferative assay		72 hrs		Antiproliferative activity against human Raji cells after 72 hrs by MTT assay, IC50 = 0.00995 μM.	28325601
KARPAS422	Growth inhibition assay				Growth inhibition of human KARPAS422 cells by CCK8 assay, GI50 = 0.68 μM.	28835805
Pfeiffer	Growth inhibition assay				Growth inhibition of human Pfeiffer cells by CCK8 assay, GI50 = 0.74 μM.	28835805
Saos-2	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
SK-N-SH	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells	29435139
MG 63 (6-TG R)	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells	29435139
NB1643	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells	29435139
OHS-50	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells	29435139
Rh41	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells	29435139
SK-N-MC	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells	29435139
NB-EBc1	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells	29435139
LAN-5	qHTS assay				qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells	29435139
SUDHL6	Antiproliferative assay		72 hrs		Antiproliferative activity against human SUDHL6 cells after 72 hrs by CCK8 assay, IC50 = 0.65 μM.	29534936
RPMI8226	Antiproliferative assay		72 hrs		Antiproliferative activity against human RPMI8226 cells after 72 hrs by MTT assay, IC50 = 5.49 μM.	29534936
Raji	Antiproliferative assay		72 hrs		Antiproliferative activity against human Raji cells after 72 hrs by MTT assay, IC50 = 9.95 μM.	29534936
SU-DHL6	Growth inhibition assay				Growth inhibition of human SU-DHL6 cells by CellTiter-Glo assay, GI50 = 0.042 μM.	29601991
MOLM13	Growth inhibition assay		72 hrs		Growth inhibition of human MOLM13 cells after 72 hrs by CellTiter-Glo luminescent assay, GI50 = 1.7 μM.	30053721
MOLM14	Growth inhibition assay		72 hrs		Growth inhibition of human MOLM14 cells after 72 hrs by CellTiter-Glo luminescent assay, GI50 = 6.4 μM.	30053721
MOLM14	Antitumor assay	100 mg/kg	14 days		Antitumor activity against human MOLM14 cells xenografted in nu/nu mouse assessed as tumor growth inhibition at 100 mg/kg, po administered daily via gavage dosed for 14 days and measured daily during compound dosing relative to control	30053721
MOLM14	Antitumor assay	100 mg/kg	14 days		Antitumor activity against human MOLM14 cells xenografted in nu/nu mouse assessed as induction of apoptosis at 100 mg/kg, po administered daily via gavage dosed for 14 days and measured daily during compound dosing by TUNEL based assay	30053721
MOLM14	Antitumor assay	100 mg/kg	14 days		Antitumor activity against human MOLM14 cells xenografted in nu/nu mouse assessed as inhibition of tumor proliferation 100 mg/kg, po administered daily via gavage dosed for 14 days and measured daily during compound dosing by Ki-67 labelling based immunoh	30053721
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Chemische informatie, Opslag en Stabiliteit (Chemical Information, Storage & Stability)

Moleculair gewicht	415.42	Formule	C₂₂H₁₈FN₇O	Opslag (Vanaf de ontvangstdatum)	3 jaar-20°Cpoeder
CAS-nr.	870281-82-6	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	GS-1101			Smiles	CCC(C1=NC2=C(C(=CC=C2)F)C(=O)N1C3=CC=CC=C3)NC4=NC=NC5=C4NC=N5

Oplosbaarheid (Solubility)

In vitro
Batch:

DMSO : 83 mg/mL (199.79 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Moleculair gewicht
=	×	×

Verdunningscalculator Moleculair gewicht calculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in het gedeelte Oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-mastervloeistof: mg geneesmiddel vooraf opgelost in μL DMSO ( Concentratie mastervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de partij geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH₂O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme (Mechanism of Action)

Targets/IC₅₀/Ki	p110δ (Cell-free assay) 2.5 nM p110γ (Cell-free assay) 89 nM
In vitro	Idelalisib (CAL-101) is niet gevoelig voor andere PI3K klasse I-subeenheden, waaronder p110α, p110β, en p110γ. Het blokkeert specifiek FcϵR1 p110δ-gemedieerde CD63-expressie met een EC50 van 8 nM in primaire basofielen. Deze verbinding vertoont een grotere activiteit in B-cel acute lymfoblastische leukemie (B-ALL) en chronische lymfatische leukemie (CLL) cellen vergeleken met acute myeloïde leukemie (AML) en myeloproliferatieve neoplasma (MPN) cellen. Het produceert de reductie in pAktS473, pAktT308, en het stroomafwaartse doelwit S6 in SU-DHL-5, KARPAS-422 en CCRF-SB cellen met een EC50 van 0,1 tot 1,0 μM. Het induceert selectieve cytotoxiciteit in CLL-cellen onafhankelijk van IgVH-mutatiestatus of interfase-cytogenetica, voornamelijk via een caspase-afhankelijk mechanisme. De verbinding induceert cytotoxiciteit bij voorkeur in CLL-cellen vergeleken met normale B-cellen, zonder cytotoxiciteit te produceren in andere hematopoëtische cellen, vergeleken met LY294002. Het heeft geen direct cytotoxisch potentieel voor T-cellen en natuurlijke killercellen (NK-cellen). Het kan de productie van inflammatoire cytokines, zoals IL-6, IL-10, TNF-α, en IFN-γ, en activerings-geïnduceerde cytokines, zoals CD40L, remmen. Het antagoniseert ook CD40L-gemedieerde CLL-celoverleving. Het induceert een accumulatie van cellen in G1 en een afname van de S-fase populatie in L1236 en L591 cellen, wat deze verbinding aanduidt als een nieuwe strategie voor de behandeling van Hodgkin-lymfoom (HL).
Kinase Assay	PI3K assay
Kinase Assay	De PI3K assay wordt uitgevoerd op volledige celextracten van CLL- of normale B-cellen. Er wordt een PI3K ELISA assay uitgevoerd. Kortom, volledige celextracten worden toegevoegd aan een mengsel van PI(4,5)P2-substraat en reactiebuffer die adenosinetrifosfaat (ATP) bevat, en mogen bij kamertemperatuur incuberen. De reactie wordt gestopt door toevoeging van PI(3,4,5)P3-detector gemengd met EDTA (ethyleendiaminetetraazijnzuur) en mag 1 uur bij kamertemperatuur incuberen. Daarna wordt het mengsel van elke put overgebracht naar een PI3K ELISA-plaat en mag 1 uur incuberen. Platen worden gewassen en vervolgens 30 minuten geïncubeerd met secundaire detector. Platen worden opnieuw gewassen en een 3,3′,5,5′-tetramethylbenzidine-oplossing wordt toegevoegd gedurende 5 minuten, waarna H2SO4 wordt toegevoegd om alle reacties te stoppen. Platen worden afgelezen op 450 nm op een Labsystems 96-well plaatlezer.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/20959606/ [2] https://pubmed.ncbi.nlm.nih.gov/20522708/ [3] https://pubmed.ncbi.nlm.nih.gov/22210877/ [4] https://pubmed.ncbi.nlm.nih.gov/24625684/

Toepassingen (Applications)

Methoden	Biomarkers	Afbeeldingen	PMID
Western blot	PUMA / p53 Bim / Bcl-xl / Bid / Mcl-1 p-p65 p-AKT / AKT Cleaved caspase 3 / Cleaved caspase 9 Mcl-1 / Bcl-2 / Bid / Bcl-xl / Noxa / Bak / Bax p-FoxO3a / FoxO3a Akt(T308) / PDK1(S241) / GSK-3β(S9)		28008149
Growth inhibition assay	Cell viability Cell viability		28008149

Informatie klinische proef (Clinical Trial Information)

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Rekrutering	Aandoeningen	Sponsor/Medewerkers	Startdatum	Fasen
NCT03582098	Completed	Chronic Lymphocytic Leukaemia	Gilead Sciences	September 12 2018	--
NCT03151057	Terminated	B Cells-Tumors\|B Cell Chronic Lymphocytic Leukemia\|Follicular Lymphoma\|Mantle Cell Lymphoma\|Large B-Cell Diffuse Lymphoma of Bone (Diagnosis)	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins\|Gilead Sciences	July 31 2018	Phase 1
NCT03568929	Completed	Follicular Non-Hodgkin''s Lymphoma Refractory	Gilead Sciences	May 25 2018	--

Veelgestelde vragen (Frequently Asked Questions)

Vraag 1:
What is the recommended dose and the route of administration for it in mouse studies?

Antwoord:
According to the following paper, it can be used by I.V. administration at the concentration of 40 mg/kg. https://www.ncbi.nlm.nih.gov/pubmed/24625684

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
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C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):