Wednesday, April 22, 2015

Drugs in Clinical Pipeline: AMG-900

AMG-900 [N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine] an orally bioavailable, potent, and selective pan-aurora kinase inhibitor with activity in multidrug resistance (MDR) tumor cell lines. AMG 900 inhibits the enzyme activity of all 3 aurora kinase family members with IC50 values of 5 nM or less (IC50 A/B/C = 5/4/1/ nM). To determine the specificity of AMG 900 across the kinome, a panel of 26 kinases was screened and only MAPK14 (IC50 = 53 nM) and TYK2 (IC50 = 220 nM) enzymes were inhibited (greater than 50%) at concentrations of less than 500 nM. Further screening was performed against a panel of 353 distinct kinases, using an ATP site-dependent competition binding assay. AMG 900 exhibited low nanomolar binding affinity for aurora kinases (Kd A/B/C = 3/2/1 nM) as well as interactions (Kd less than 50 nM) with DDR1, DDR2, and LTK receptor tyrosine kinases [1].

Important findings about AMG-900:

1. AMG 900 is a potent and highly selective pan-aurora kinase inhibitor.
2. Effects of AMG 900 on proliferating cells are consistent with inhibition of aurora-B activity.
3. AMG 900 blocks the proliferation of multiple human tumor cell lines including cell lines resistant to paclitaxel, AZD1152, MK-0457, and PHA-739358.
4. AMG 900 inhibits the phosphorylation of histone H3 and suppresses the growth of human tumor xenografts in vivo.

It is developed at Amgen Labs. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Together, these features distinguish AMG 900 from other antimitotic drugs as well as 3 other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358). These key attributes contribute to the profile of this attractive clinical candidate; AMG 900 has entered phase 1 evaluation in adult patients with advanced cancers.

The activity of AMG-900 is as follows:

IC50 (AURKA enzyme assay) = 5 nM; Kd = 3 nM
IC50 (AURKB enzyme assay) = 4 nM; Kd = 2 nM
IC50 (AURKC enzyme assay) = 1 nM; Kd = 1 nM
IC50 (MAPK14 enzyme assay) = 53 nM
IC50 (TYK2 enzyme assay) = 220 nM

Common Name: AMG-900
Synonyms: AMG-900; AMG 900
IUPAC Name: N-(4-((3-(2-aminopyrimidin-4-yl)pyridin-2-yl)oxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine
CAS Number: 945595-80-2
Mechanism of Action: Kinase Inhibitor; pan-Aurora Kinase Inhibitor
Indication: Various Cancers
Development Stage: Phase I
Company: Amgen Labs

Aurora kinases are essential mitotic regulators and their potential role in tumorigenesis makes them attractive targets for anticancer therapy. In mammalian cells, the aurora family of serine/threonine protein kinases is composed of 3 paralogous genes (aurora-A, -B, and -C). Aurora-A and -B are essential regulators of mitotic entry and progression, whereas aurora-C function is primarily restricted to male meiosis during spermatogenesis. Aurora-A can function as an oncogene and is amplified in a subset of human tumors. The expression of aurora-A and -B is frequently elevated in human cancers and is associated with advanced clinical staging.

AMG 900 is active in all of the tested tumor cell lines at low nanomolar concentrations, suggesting that it can inhibit the proliferation of tumor cells irrespective of genomic alterations or tumor origin. It is possible that the underlying profile of genetic and epigenetic modifications in tumor cells may play an important role in determining the fate of remnant cells that survive AMG 900 treatment.

AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans [2]. 

AMG 900 Metabolism in rats

The metabolism of AMG 900 was investigated in both male and female rats. Researchers conducted studies in bile-duct catheterized (BDC) rats where bile, urine and plasma were analyzed to obtain metabolism profiles for each gender. These studies identified gender differences in the metabolism profiles in bile. Bile contained the majority of the drug related material and contained little unchanged AMG 900 which indicated that metabolism was the prominent process in drug elimination. Although bile contained the same metabolites for both genders, the amount of specific metabolites differed. CYP phenotyping identified the prominent isoforms as being gender specific or biased in the oxidative metabolism of AMG 900. The metabolism in male rats favored both CYP2C11 and CYP2A2 whereas females favored the CYP2C12. Male rats metabolized AMG 900 primarily through hydroxylation with subsequent sulfate conjugation on the pyrimidinyl-pyridine side-chain whereas female rats favored a different oxidation site on the thiophene ring's methyl group, which is then metabolized to a carboxylic acid with subsequent conjugation to an acyl glucuronide [3].

1. Payton, M.; et. al. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res 2010, 70(23), 9846-9854.
2. Huang, L.; et. al. In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases. Xenobiotica 2011, 41(5), 400-408.
3. Waldon, D.; et. al. Gender effects on rat metabolism of AMG 900, an orally available small molecule aurora kinase inhibitor. Drug Metab Lett 2011, 5(4), 290-297.
4. Cee, V. J.; et. al. Aurora kinase modulators and method of use. WO2007087276A1
5. A Phase 1 First-in-Human Study Evaluating AMG 900 in Advanced Solid Tumors. NCT00858377 (retrieved on 22-04-2015)