Thursday, August 6, 2015

Drugs in Clinical Pipeline: Luminespib

Luminespib [5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide] is a novel resorcinylic isoxazole amide heat shock protein 90 (HSP90) inhibitor. 

Luminespib potently inhibits HSP90 (Kd = 1.7 nM) and proliferation of human tumor cells with GI50 values of approximately 2 to 40 nM, inducing G1-G2 arrest and apoptosis [1]. Luminespib was the most potent synthetic small-molecule HSP90 inhibitor when reported in year 2008. It is still one of few synthetic inhibitors of HSP90 that have high potency.

The 50% inhibitory concentration (IC50) for Luminespib in competitive binding fluorescence polarization assay gave a value of 21 ± 16 nM against HSP90β and of 7.8 ± 1.8 nM for HSP90α. Inhibitory kinetics were competitive and the Ki values were 9.0 ± 5.0 nM and 8.2 ± 0.7 nM for HSP90α and HSP90β, respectively. Isothermal calorimetry showed a very high binding affinity to HSP90β with a Kd of 1.7 ± 0.5 nM. The enthalpy of binding of Luminespib is -12.24 kcal/mol. The entropy of binding of Luminespib is almost negligible (0.19 cal/mol/K), indicating that the binding event is driven essentially exclusively by enthalpy (i.e., bonding interactions). Luminespib exhibits the tightest binding of any small-molecule HSP90 ligand yet reported. The IC50 values for Luminespib against the HSP90 family members GRP94 and TRAP-1 were 535 ± 51 nM (Ki = 108 nM) and 85 ± 8 nM (Ki = 53 nM), respectively, indicating weaker potency than for HSP90 [1].

Luminespib was discovered in a multiparameter lead optimization program based on a high-throughput screening hit methodology developed jointly by The Institute of Cancer Research, UK and the pharmaceutical company Vernalis. It has been licensed to Novartis. It has been licensed to Novartis. Luminespib activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. Pre-clinical studies proved that Luminespib acts via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. These results helped Luminespib to enter clinical trials for various cancers including breast cancers [2].

The activity of Luminespib is as follows:

IC50 (HSP90β binding assay) = 21 ± 16 nM; Ki = 8.2 ± 0.7 nM
IC50 (HSP90α binding assay) = 7.8 ± 1.8 nM; Ki = 9.0 ± 5.0 nM

Common Name: Luminespib
Synonyms: AUY-922; AUY922; AUY 922; NVP-AUY-922; NVP-AUY922; VER-52296; VER52296; VER 52296
IUPAC Name: 5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl) phenyl) isoxazole-3-carboxamide
CAS Number: 747412-49-3
Mechanism of Action: HSP90 Inhibitor
Indication: Various Cancers
Development Stage: Phase II
Company: The Institute of Cancer Research, Vernalis Ltd./Novartis

Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis.

Luminespib potently inhibited the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. Luminespib induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion-hallmarks of HSP90 inhibition. Intravenous acute administration of Luminespib to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels [2].

Luminespib potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 less than 100 nM. IC100 value less than 40 nM was seen in 36 of 41 lines. Consistent gene expression changes after Luminespib exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase after exposure. Luminespib slowed growth of A549 (KRAS-mutant) xenografts and achieved tumor stability and decreased EGF receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR-tyrosine kinase inhibitors in the EGFR gene [3].

1. Eccles, S. A.; et. al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 2008, 68(8), 2850-2860.
2. Jensen, M. R.; et. al. NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Research 2008, 10, R33.
3. Garon, E. B.; et. al. The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth. Mol Cancer Ther 2013, 12(6), 890-900.