Thursday, June 4, 2015

Idelalisib I Kinase Inhibitor | PI3Kdelta Inhibitor | Treatment of Chronic Lymphocytic Leukemia | Treatment of Follicular B-cell Non-Hodgkin Lymphoma | Treatment of Small Lymphocytic Lymphoma

Common name: Idelalisib; CAL-101; CAL 101; CAL101; GS-1101; GS 1101; GS1101; Zydelig
Trademarks: Zydelig
Molecular Formula: C22H18FN7O
CAS Registry Number: 870281-82-6
CAS Name: 5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone
Molecular Weight: 415.42 g/mol
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
Mechanism of Action: Protein Kinase Inhibitor; Kinase Inhibitor; PI3K Inhibitor; PI3Kdelta Inhibitor; Antineoplastic Drugs 
Indication: Various Cancers; Treatment of Chronic Lymphocytic Lymphoma (CLL); Treatment of Follicular B-cell non-Hodgkin Lymphoma (FL); Treatment of Small Lymphocytic Lymphoma (SLL) 
Status: Launched 2014 (US, EU)
Originator: Calistoga Pharmaceuticals/Gilead

Idelalisib: 2D and 3D Structure

Idelalisib as Medicine:

The first-in-class Phosphatidylinositol-3-kinase p110δ (PI3Kδ) inhibitor Idelalisib (Zydelig) is approved in the treatment of chronic lymphocytic leukemia (CLL) and for 2 types of lymphoma in patients who have relapsed after previous treatment. The US Food and Drug Administration (FDA) granted a full approval for Idelalisib in relapsed CLL, specifically for its use in combination with rituximab (Rituxan) in patients for whom rituximab alone would be considered appropriate therapy due to other existing medical conditions (comorbidities).

The approval of this indication was based on a placebo-controlled trial in 220 patients that was stopped early for benefit. The first prespecified interim analysis showed a significantly longer progression-free survival in patients treated with idelalisib plus rituximab (10.7 months) compared with those on placebo plus rituximab (5.5 months). Results from a second interim analysis continued to show a statistically significant improvement, the FDA noted [1].

The other two approved for indications are:

Follicular B-cell non-Hodgkin Lymphoma (FL) when the disease has come back after treatment with at least two prior medicines.
Small Lymphocytic Lymphoma (SLL) when the disease comes back after treatment with at least two prior medicines.

Idelalisib had both breakthrough therapy designation and orphan drug designation.

The FDA also granted accelerated approval for Idelalisib for use in relapsed follicular B-cell non-Hodgkin's lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL), another type of non-Hodgkin's lymphoma. Idelalisib is intended to be used in patients who have received at least 2 prior systemic therapies. These lymphoma patients had become refectory to both rituximab and alkylating agents but when treated with Idelalisib, the results showed an overall response rate of 54% in patients with relapsed FL and 58% in patients with SLL [2].

Idelalisib [5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one] is an oral, highly selective and potent small molecule inhibitor of Phosphatidylinositol-3-kinase p110δ (PI3Kδ). Idelalisib was 40- to 300-fold more selective for p110d relative to other PI3K class I enzymes (IC50 p110δ = 2.5 nM; p110α, p110β, and p110γ IC50 were 820, 565, and 89 nM, respectively). Greater selectivity (400- to 4000-fold) was seen against related kinases C2β, mTOR (IC50 for both greater than 1000 nM), hVPS34, DNA-PK (IC50 = 978, 6729 nM, respectively), whereas no activity was observed against a panel of 402 diverse kinases at 10µM. Idelalisib is currently under clinical evaluation in patients with B-cell malignancies [3].

In cell-based assays, Idelalisib had 240- to 2500-fold selectivity for PI3Kδ over the other class I PI3K isoforms. The following results highlight this selectivity:

In fibroblasts, the receptor tyrosine kinase platelet-derived growth factor receptor signals through p110α and the G-protein–coupled receptor for lysophosphatidic acid (LPA) signals through p110 β. Researchers stimulated murine embryonic fibroblasts with PDGF or LPA and monitored phosphorylation of Akt to measure pathway activation. Idelalisib reduced PDGF-induced pAkt by only 25% at 10 µM, whereas the positive control, PI-103, had a half-maximal effective concentration (EC50) of 90 nM. Idelalisib inhibited LPA-induced pAkt with an EC50 of 1.9 µM.

Expression of p110δ and p110γ is normally restricted to leukocytes. In basophils, FcεRI signals through p110δ, whereas formyl-methionyl-leucyl-phenylalanine (fMLP) signals through G-protein-coupled receptor- p110γ, and activation through either stimulus results in surface expression of CD63 that can be monitored by flow cytometry. CAL-101 blocked FcεRI p110δ-mediated CD63 expression with an EC50 of 8 nM, whereas formyl-methionyl-leucyl-phenylalanine activation of p110γ was inhibited with an EC50 of 3.0 µM.

Idelalisib as Chemical Compound:

Idelalisib is a quinazolinone derivative. Specifically it is a quinazolin-4-one molecule with a purine unit present in it. Other important chemical classifications are:

1. Fluoro compound
2. Purine derivatives
3. Quinazolin-4-one derivatives
4. Quinazolinones
5. Alkylhalides


Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes. Common adverse effects include diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Idelalisib carries a boxed warning alerting patients/healthcare professionals of fatal and serious toxicities that can occur, including liver toxicity, diarrhea and colon inflammation (colitis), lung inflammation (pneumonitis), and intestinal perforation.

1. Furman, R. R.; et. al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014, 370(11), 997-1007.
2. Keating, G. M.; et. al. Idelalisib: a review of its use in chronic lymphocytic leukaemia and indolent non-Hodgkin's lymphoma. Target Oncol 2015, 10(1), 141-151.
3. Lannutti, B. J.; et. al. CAL-101, a p110d selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 2011, 117(2), 591-594.
4. FDA approves Zydelig for three types of blood cancers. Food and Drug Administration. July 23, 2014.
5. European Medicines Agency recommends approval of two new treatment options for rare cancers. European Medicines Agency. July 25, 2014.