Friday, October 21, 2016

Drugs in Clinical Pipeline: TGR-1202 | Orphan Drug | Kinase Inhibitor | Phosphoinositide 3-kinase delta (PI3Kδ) Inhibitors | Cancer Drug

TGR-1202 [(S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one] is a potent, orally available, small molecule selective phosphoinositide 3-kinase (PI3K) delta (PI3Kδ;  IC50 = 22.23 nM) kinase inhibitor with high selectivity over all other PI3K isoforms (48 – 10000 times) as well that for a 441-kinase panel. The selectivity and activity of TGR-1202 is credited to its design with a unique backbone compared to other PI3K inhibitors in development [1, 2].

Structure for TGR-1202
TGR-1202 : 2D and 3D Structure

TGR-1202 is currently under clinical development for patients with relapsed and refractory hematological malignancies.
On Aug 24, 2016 TG Therapeutics, Inc. announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for the oral, next generation PI3K-delta (PI3Kδ) inhibitor, TGR-1202, in the treatment of patients with Chronic Lymphocytic Leukemia (CLL).

PI3K-delta (PI3Kd) as Cancers Targets
The PI3K plays a major role in many aspects of cellular biology and is often hyper-activated in human cancers. The PI3K family of enzymes has multifunctional roles regulating cellular growth, proliferation, differentiation, motility, intracellular trafficking, and metabolism. Three distinct classes of PI3K (class I, II and III) have been characterized and grouped according to their structure and function.
Biochemical, cellular and genetic evidences have accumulated for the past three decades defining the phosphoinositide 3-kinase (PI3K) and downstream signaling as an important oncogenic driver in human cancers and have fueled attempts at targeting this axis by pan-PI3K [targeting all four class I isoforms: PI3K-aplha (PI3Kα), PI3K-beta (PI3Kβ), PI3K-delta (PI3Kδ), or PI3K-gamma (PI3Kγ)] or isoform-specific inhibitors. PI3K catalytic subunit mediates phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to yield phosphatidylinositol-3,4,5-trisphosphate (PIP3), a second messenger that functions as an anchor at the cellular membrane to assemble and activate downstream signaling complexes, including the protein kinase B (AKT) kinase. The class IA PI3K signaling pathway is activated in human cancers due to mutational activation, or amplification of genes encoding the catalytic subunits, or by inactivation of phosphatases such as PTEN that catabolize PIP3.
Phosphoinositide 3-kinase p110 isoform d (PI3K-delta or PI3Kδ) is hyperactivated in B-cell malignancies and plays a pivotal role in the B-cell receptor (BCR) pathway, a key oncogenic driver in B-cell malignancies. The near exclusive expression of the PI3K-delta (PI3Kδ) isoform in hematopoietic cells makes them target of choice for such cases.
Idelalisib is an orally bioavailable ATP-competitive kinase inhibitor that targets the PI3K-delta (PI3Kδ) with high potency and selectivity. Idelalisib is the first PI3K inhibitor approved by the regulatory agencies for the treatment landscape of indolent B-cell malignancies.
TGR-1202 is designed as a PI3K-delta (PI3Kδ) isoform inhibitor with the purpose to overcome limitations (sideeffects) of first generation PI3K-delta (PI3Kδ) isoform inhibitors.

Mechanism of Action in TGR-1202
TGR-1202 is an orally available PI3K delta (PI3Kδ) kinase inhibitor, targeting the delta isoform with nanomolar potency and several fold selectivity over the alpha, beta, and gamma isoforms [PI3K-aplha (PI3Kα), PI3K-beta (PI3Kβ), and PI3K-gamma (PI3Kγ)]. Inhibition of PI3K delta (PI3Kδ) signaling with TGR-1202 has demonstrated robust activity in numerous pre-clinical models and primary cells from patients with hematologic malignancies.

Dosages and Approvals:
TGR-1202 (Tradename: -) is a next generation PI3K-delta (PI3Kδ) inhibitor with a unique structure and activity profile distinct from other PI3K-delta (PI3Kδ) inhibitors in development. Incozen Therapeutics and Rhizen Pharmaceuticals discovered TGR-1202 (then known as RP-5264) and TG Therapeutics is credited with the development of TGR-1202.
TG Therapeutics has claimed that TGR-1202 is blessed with a prolonged half-life and accumulation that enables once-daily dosing. Moreover, the drug has a differentiated safety profile from other PI3K-delta (PI3Kδ) inhibitors in development, notably with respect to hepatic toxicity and colitis to date.
On Aug 24, 2016 TG Therapeutics, Inc. announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for the oral, next generation PI3K-delta (PI3Kδ) inhibitor, TGR-1202, in the treatment of patients with Chronic Lymphocytic Leukemia (CLL).
TGR-1202 is in clinical trials [3, 4].

Reported Activities for TGR-1202
The enzyme activity for TGR-1202 was determined using a PI3K HTRF Assay Kit. It proved to be a potent nanomolar inhibitor for PI3K-delta (PI3Kδ) with IC50 value of 22.23 nM. The 50% inhibition values for the other class IA isoforms are reported as selectivity ratios with TGR-1202 being more than 10000 times more selective against PI3K-aplha (PI3Kα) isoform. The selectivity is more than 50 times against both PI3K-beta (PI3Kβ) and PI3K-gamma (PI3Kγ) isoforms [1, 2].
In cell based assays, TGR-1202’s specificity towards PI3K-delta (PI3Kδ) was determined in an IgM-induced B cell proliferation assay. For selectivity against PI3K-aplha (PI3Kα), PI3K-beta (PI3Kβ), and PI3K-gamma (PI3Kγ) isoforms, NIH-3T3 or RAW macrophages were seeded in a 6-well tissue culture plate and incubated with compounds at the desired concentrations followed by 20 ng/ml PDGF, 5 µM LPA, or 50 ng/ml c5a.

IC50 (Inhibition of PI3Kδ Kinase Activity) = 22.23 nM
EC50 (Inhibition of PI3Kδ Dependent B cell Proliferation Assay) = 24.27 nM 
Selectivity ratios in enzyme assay [PI3K-aplha (PI3Kα), PI3K-beta (PI3Kβ), and PI3K-gamma (PI3Kγ)] = greater than 10000, greater than 50, greater than 48.
Selectivity ratios in cell-based assay [PI3K-aplha (PI3Kα), PI3K-beta (PI3Kβ), and PI3K-gamma (PI3Kγ)] = greater than 10000, greater than 34, greater than 17.


Common name: TGR-1202; TGR1202; TGR 1202; RP5264; RP 5264; RP-5264
Trademarks: -
Molecular Formula: C31H24F3N5O3
CAS Registry Number: 1532533-67-7
CAS Name: (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one
Molecular Weight: 571.55
InChI: InChI=1S/C31H24F3N5O3/c1-15(2)41-24-9-7-18(12-22(24)34)27-26-30(35)36-14-37-31(26)39(38-27)16(3)29-25(17-5-4-6-19(32)11-17)28(40)21-13-20(33)8-10-23(21)42-29/h4-16H,1-3H3,(H2,35,36,37)/t16-/m0/s1
Mechanism of Action: Kinase Inhibitors; Phosphoinositide 3-kinase delta (PI3Kδ) Inhibitors
Activity: Treatment for Chronic Lymphocytic Leukemia (CLL); Cancer Drug
Status: Under Clinical Trials
Chemical Class: Small molecules; Flourine containing; Benzylamines; Ether containing; Fluorobenzenes
Originator: Incozen Therapeutics and Rhizen Pharmaceuticals/TG Therapeutics
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