Sunday, February 5, 2017

Drugs in Clinical Pipeline: TAS-116 | Heat Shock Protein (HSP90) Inhibitor | Treatment of Tumors | Cancer Drug

TAS-116 [3-ethyl-4-[3-(1-methylethyl)-4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-1H-pyrazolo[3,4-b]pyridin-1-yl]benzamide] is a small molecule selective heat shock protein 90 (HSP90α/β) inhibitor. It shows greater specific binding to HSP90α and β than to the highly homologous HSP90 family members GRP94 and TRAP1 [1].

Structure of TAS-116
TAS-116 : 2D and 3D Structure

Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90 α and β alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue.

TAS-116 shows favorable pharmacokinetics and a reduced ocular toxicity profile, possibly due to its lower distribution in retinal tissue than in plasma in rats. Moreover, TAS-116 shows superior anti-tumor effects in several tumors including multiple myeloma (MM) and lung carcinoma in vitro and in vivo. TAS-116 represents a novel molecule with promising therapeutic potential [1, 2].

Heat Shock Protein (HSP90) as Drug Target:
Protein folding in the cell is organised by molecular chaperones. The major chaperone systems are adenosine triphosphate (ATP) regulated mechanisms conserved from bacteria to man namely heat shock proteins, Hsp60, Hsp70, Hsp90 and Hsp100. These chaperone classes differ dramatically in sequence and structure, which is highlighted by their different functions [3].
The heat shock protein 90 (Hsp90) family is of particular interest because some of its members are especially dedicated to signal transduction. Hsp90 clients include many of the cancer-related proteins necessary for tumor development, including receptor tyrosine kinases, signal transducers, cell-cycle regulators, and transcriptional factors. Hsp90 is reported to be specifically overexpressed and to exist as activated multi-chaperone complexes in cancer cells and cancer tissues. Some authors have used the word “addiction” to highlight the preference of the cancer cells of Hsp90 for their survival and proliferation.
In human cells there are four Hsp90 isoforms: the heat shock inducible Hsp90α and the constitutively expressed Hsp90β both in the cytosol, mitochondrial Trap1 and Grp94 located in the endoplasmic reticulum (ER).
Hsp90β is one of the most abundant proteins in the human cytosol, it makes up 1-2% of cytosolic protein. Hsp90 can suppress protein aggregation in vitro, independent of ATP. In vivo, however, ATPase activity is essential for the Hsp90 working cycle hence cell viability. Mutant Hsp90s with either faster or slower ATPase rate result in temperature-sensitive growth phenotypes and they are unable to fully activate their client proteins.
Heat Shock Protein 90 (HSP90) has therefore emerged as an attractive target for cancer interventions, and many HSP90 inhibitors have been developed.

Mechanism of Action in TAS-116:

TAS-116 is an orally available, small-molecule and specific heat shock protein α and β (HSP90 α and β) inhibitor. It showed negligible affinity for other two isoforms namely GRP4 and TRAP1. TAS-116 was discovered during a multi-parameter lead optimization campaign to have high target-selectivity for certain HSP90 proteins.

TAS-116 inhibited geldanamycin-FITC binding to HSP90 proteins with Ki values of 34.7 nM, 21.3 nM, greater than 50 uM, and greater than 50 uM for HSP90α  and  HSP90β, GRP94, and TRAP1, respectively. Furthermore, TAS-116 did not inhibit other ATP-ases such as HSP70 (IC50, more than 200 uM) or any of 48 different protein kinases tested (IC50, all more than 30 uM).

Dosages and Approvals:
TAS-116 (Tradename: -) is being developed by Taiho Pharmaceutical (a subsidiary of Otsuka Holdings). TAS-116 is under Phase-I trials in patients with solid tumors and Phase-II clinical trials in Gastrointestinal stromal tumours (GST).

Measured Activities for TAS-116: 
Ki (Inhibition of geldanamycin–FITC binding to HSP90α) = 34.7 ± 8.4 nM
Ki (Inhibition of geldanamycin–FITC binding to HSP90β) = 21.3 ± 3.0 nM
Ki (Inhibition of geldanamycin–FITC binding to GRP94) = greater than 50 uM
Ki (Inhibition of geldanamycin–FITC binding to TRAP1) = greater than 50 uM
%Inh (Inhibition of RPS6KB1 Kinase Activity @ 10 uM TAS-116) = 22%
%Inh (Inhibition of CDK2 Kinase Activity @ 10 uM TAS-116) = 10%
%Inh (Inhibition of STK3 Kinase Activity @ 10 uM TAS-116) = 19%
%Inh (Inhibition of SRC Kinase Activity @ 10 uM TAS-116) = 4%

IC50 (HSP90 binding-activity) = 0.10 uM


Common name: TAS-116; TAS116; TAS 116
Trademarks: -
Molecular Formula: C25H28N8O
CAS Registry Number: 1260533-36-5
CAS Name: 3-ethyl-4-(3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzamide
Molecular Weight: 454.53
InChI: InChI=1S/C25H26N8O/c1-5-16-10-17(24(26)34)6-7-20(16)33-25-22(23(30-33)15(2)3)21(8-9-27-25)32-13-19(28-14-32)18-11-29-31(4)12-18/h6-15H,5H2,1-4H3,(H2,26,34)
Mechanism of Action: Heat Shock Protein 90 (HSP90) Inhibitor; HSP90 α/β Inhibitor
Activity: Treatment for Tumors; Cancer Drug
Status: Under Phase Trials
Chemical Class: Small molecules; Amide containing; Pyrazolyl compound; Imidazolyl compound; Benzene containing; Azabicyclo compound
Originator: Taiho Pharmaceutical
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