Drugs in Clinical Pipeline: PF-03814735

PF-03814735 [N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidine-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide] is a novel, potent, orally bioavailable, reversible inhibitor of both AURKA and AURKB kinases. Although PF-03814735 produces significant inhibition of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases.

In in vitro enzymatic assays, the trifluoromethylpyrimidine derivative PF-03814735 was identified as a potent inhibitor of the AURKB and AURKA kinases, with IC₅₀ values of 0.8 nM and 5 nM, respectively. The kinetics of inhibition of recombinant AURKB kinase by PF-03814735 indicated that inhibition was ATP competitive. PF-03814735 produced significant inhibition of several other protein kinases in recombinant kinase enzymatic assays. Of 220 kinases evaluated, 19 others showed greater than 90% inhibition at 100 nM of PF-03814735. The IC₅₀ values of PF-03814735 for a subset of these kinases revealed the greatest potency for AURKA and AURKB, followed by Flt1, FAK, TrkA, Met, and FGFR1 (IC₅₀ = 10, 22, 30, 100 and 100 nM, respectively). Thus, PF-03814735 was shown to be a potent inhibitor of AURKA and AURKB kinases as well as several other protein kinases in enzymatic assays [1].

A product from Pfizer, PF-03814735 is under Phase I trials for patients with advanced solid tumors.

The activity of PF-03814735 is as follows:

IC₅₀ (AURKB enzyme assay) = 0.8 ± 0.6 nM

IC₅₀ (AURKA enzyme assay) = 5 ± 3 nM

IC₅₀ (FLT1 enzyme assay) = 10 nM

IC₅₀ (FAK enzyme assay) = 22 nM

IC₅₀ (TRKA enzyme assay) = 30 nM

IC₅₀ (MET enzyme assay) = 100 nM

IC₅₀ (FGFR1 enzyme assay) = 100 nM

Kinases that showed more than 90% inhibition at 100 nM of PF-03814735 include CDK5/p35; Flt3(D835Y); ARK5; NEK2; Flt4; Ret; MLK1; TrkB; Fer; JAK2; Flt3; MST3; CDK5/p25; MST2; Rsk3. Abl(T315I) showed 69%, and Abl showed 50% inhibition at same concentration.

Common Name: PF-03814735

Synonyms: PF-03814735; PF03814735; PF 0381473

IUPAC Name: N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidine-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide

CAS Number: 942487-16-3

SMILES:CC(=O)NCC(=O)N1C2CCC1C3=C2C=CC(=C3)NC4=NC=C(C(=N4)NC5CCC5)C(F)(F)F

Mechanism of Action: Kinase Inhibitor; AURKA Inhibitor; AURKB Inhibitor

Indication: Various Cancers

Development Stage: Phase I

Company: Pfizer

The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. In mammals, three related Aurora kinases known as Aurora-A (Aurora2, AURKA), Aurora-B (Aurora1, AURKB), and Aurora-C (Aurora3, AURKC) have been identified. Although these kinases have significant sequence homology, their subcellular localization, timing of activation, and biological functions during mitosis are largely distinct from one another. Aurora1 and Aurora2 play important but distinct roles in the G2 and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer. Overall, these kinases play an important role in centrosome duplication, mitotic spindle formation, chromosome alignment, mitotic checkpoint activation, and cytokinesis.

MDA-MB-231 cells were exposed to PF-03814735 for 4 hours followed by fixation, staining for antibodies specific for various protein kinase substrates and quantitative image analysis. PF-03814735 treatment markedly reduced levels of AURKB phosphorylated on Thr 232 in cells, a sensitive marker of AURKB activity, with an IC₅₀ ~20 nM. PF-03814735 also inhibited the phosphorylation of histone H3 on Ser10, another marker of AURKB kinase activity, with an IC₅₀ ~50 nM. Researchers measured the inhibitory activity of PF-03814735 on the AURKA kinase in this cell line by the loss of cells staining positively for Aurora2 autophosphorylated on Thr288 and observed an IC₅₀ of ~150 nM. These results suggest PF-03814735 was a potent inhibitor of the AURKB and AURKA kinases in cells [1].

Inhibition of cell proliferation by PF-03814735 was evaluated against several human cell lines from various tumor types (HCT-116, HL-60, A549, and H125) as well as tumor cell lines of rat (C6), mouse (L1210), and dog (MDCK) origin. Cell lines were exposed to PF-03814735 in culture for 48 hours followed by determination of cell counts. PF-03814735 treatment resulted in a reduction in cell number relative to untreated control cultures. For this panel of cell lines, the calculated IC₅₀ for PF-03814735 was 42 to 150 nM. PF-03814735 treatment at 300 nM produced near-complete inhibition of proliferation of these cell lines tested. 

Moreover, the antiproliferative effects of PF-03814735 in vivo in mouse tumor models were also consistent with inhibition of Aurora kinases. Researchers observed reductions in levels of phosphorylated histone H3 in xenograft HCT-116 tumors at plasma concentrations associated with tumor growth inhibition in vivo and antiproliferative activity in cell culture. Although the biochemical effects on AURKA and AURKB seem to be the primary basis of the antiproliferative activity seen both in cell culture and in tumors in vivo, but that inhibition of one or more of the off-target kinases contributes to the effects of PF-03814735 cannot be ruled out either [1].

Phase I Study

In an accelerated dose-escalation study to identify the Maximum Tolerated Dose (MTD) and Recommended Phase II Dose, and to obtain proof-of-mechanism (by assessment of pH3 inhibition in tumor biopsies and FDG-PET) with PF-03814735 administered daily for 5 or 10 consecutive days in 3-week cycles,twenty patients (20) received a median of 2 cycles (1-4) across 7 dose levels from 5 to 100 mg/day for 5 days. Tumor types included colorectal (5), breast (3), NSCLC (4), SCLC (2), bladder, melanoma, ovarian, renal, head and neck and cancer of unknown primary (1 each). The dose was doubled in single patient cohorts until treatment-related grade 2 diarrhea occurred in one patient at 40 mg/day. Afterwards, cohorts included 3-7 patients with 20-50% dose increments per cohort. After a single dose, the total clearance of PF-03814735 is 1195±393 mL/hr and median terminal half-life is 19.1 hr. PK of PF-3814735 is linear [2].

In the first 16 patients, the most common treatment-related adverse events were mild to moderate diarrhea (50%), vomiting (25%), anorexia, fatigue, and nausea (19% each). Dose-limiting febrile neutropenia was observed in 2/7 patients treated at 100 mg/day [2].

References:

1. Jakubczak, J. L.; et. al. PF-03814735, an Orally Bioavailable Small Molecule Aurora Kinase Inhibitor for Cancer Therapy. Mol Cancer Ther 2010, 9(4), 883-894.
2. Jones, S. F.; et. al. Phase I accelerated dose-escalation, pharmacokinetic (PK) and pharmacodynamic study of PF-03814735, an oral aurora kinase inhibitor, in patients with advanced solid tumors: Preliminary results. J Clin Oncol 2008, 26(15 suppl), 2517.

3. ClinicalTrials.gov Phase 1 Study Of Aurora Kinase Inhibitor PF-03814735 In Patients With Advanced Solid Tumors. NCT00424632 (retrieved 25-10-2015)

Drugs in Clinical Pipeline: KW-2449

KW-2449 [(E)-(4-(2-(1H-indazol-3-yl)vinyl)phenyl)(piperazin-1-yl)methanone] is an orally available multikinase inhibitor of FMS-like receptor tyrosine kinase (FLT3), ABL, ABL-T315I, and Aurora kinase. It is currently in Phase I trials for leukemia patients. KW-2449 inhibited FLT3 and ABL kinases with half-maximal inhibitory concentration (IC₅₀) values of 0.0066 and 0.014 µM, respectively. In addition, it potently inhibited ABL-T315I, which is associated with IM resistance, with an IC₅₀ value of 0.004 µM. On the other hand, KW-2449 had little effect on PDGFRβ, IGF-1R, EGFR, and various serine/threonine kinases even at a concentration of 1 µM. Among various serine/threonine kinases examined, KW-2449 inhibited Aurora A kinase with IC₅₀ of 0.048 µM and Aurora B kinase with the equivalent potency.

The researchers at Kyowa Hakko Kirin (previously Kyowa Hakko Kogyo) aimed at designing an orally available and highly potent FLT3 inhibitor with low toxicity profile for leukemia patients. For this goal, they screened the in-house chemical libraries using several leukemia cells, which have several activated mutations in FLT3 or BCR-ABL translocation. As a result, they identified several chemo-types with different kinase inhibition profiles, intensively studied the structures of the identified chemo-types to improve the potency and selectivity, and then finally generated KW-2449 [1].

Preclinical studies revealed that KW-2449 is converted by monoamine oxidase-B (MAO-B) and aldehyde oxidase into its major metabolite M1. Metabolite M1 is 3.6-fold less potent than the parent drug. The combination of KW-2449 and metabolite can successfully inhibit FLT3 in patients, and FLT3 mutant patients treated with KW-2449 on a twice daily schedule display the typical, short-lived reduction in peripheral blasts that has been seen with the other FLT3 inhibitors in development.

The activity of KW-2449 is as follows:

IC₅₀ (FLT3 enzyme assay) = 0.0066 uM

IC₅₀ (FLT3-D835Y enzyme assay) = 0.001 uM

IC₅₀ (KIT enzyme assay) = 0.3 uM

IC₅₀ (PDFGRα enzyme assay) = 1.7 uM

IC₅₀ (ABL enzyme assay) = 0.014 uM

IC₅₀ (ABL-T315I enzyme assay) = 0.004 uM

IC₅₀ (SRC enzyme assay) = 0.4 uM

IC₅₀ (JAK2 enzyme assay) = 0.15 uM

IC₅₀ (FGFR1 enzyme assay) = 0.036 uM

IC₅₀ (AURKA enzyme assay) = 0.048 uM

Common Name: KW-2449

Synonyms: KW2449; KW-2449; KW 2449

IUPAC Name: (E)-(4-(2-(1H-indazol-3-yl)vinyl)phenyl)(piperazin-1-yl)methanone

CAS Number: 1000669-72-6

Mechanism of Action: Kinase Inhibitor; FLT3 Inhibitor; ABL Inhibitor; Aurora Kinase Inhibitor; MultiKinase Inhibitor

Indication: Various Cancers; Leukemia

Development Stage: Phase I

Company: Kyowa Hakko Kirin Pharmaceuticals

FMS-like receptor tyrosine kinase (FLT3) is a class III receptor tyrosine kinase together with cKIT, FMS, and PDGFR. FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence; subsequently, a missense point mutation at the Asp835 residue and point mutations, deletions, and insertions in the codons surrounding Asp835 within a tyrosine kinase domain of FLT3 (FLT3/KDM) have been found. FLT3 mutation is the most frequent genetic alteration in acute myeloid leukemia (AML) and involved in the signaling pathway of proliferation and survival in leukemia cells. Several large-scale studies have confirmed that FLT3/ITD is strongly associated with leukocytosis and a poor prognosis. In addition to FLT3 mutation, overexpression of FLT3 is an unfavorable prognostic factor for overall survival in AML, and it has been revealed that overexpressed FLT3 had the same sensitivity to the FLT3 inhibitor as FLT3/ITD [1]. Acute leukemia is a complex multigenetic disorder, a simultaneous inhibition of multiple protein kinases is thought to be advantageous over the increasing potency against the selective kinases.

In vitro kinase inhibition profile of KW-2449 indicated its extreme potency against FLT3 kinase. KW-2449 showed growth inhibitory activities against FLT3/ITD-, FLT3/D835Y-, and wt-FLT3/FL-expressing 32D cells, MOLM-13 and MV4;11 with half-maximal growth inhibitory concentration (GI₅₀) values of 0.024, 0.046, 0.014, 0.024, and 0.011 µM, respectively [1].

References:

1. Shiotsu, Y.; et. al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood 2009, 114(8), 1607-1617.

2. ClinicalTrials.gov Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Study of KW-2449 in Acute Myelogenous Leukemia (AML) (Protocol Number: 2449-US-002). NCT00779480. Retrieved (01-09-2015)

3. ClinicalTrials.gov An Ascending Dose Study of KW-2449 in Acute Leukemias, Myelodysplastic Syndromes, and Chronic Myelogenous Leukemia. NCT00346632. Retrieved (01-09-2015)

Drugs in Clinical Pipeline: MLN8054

MLN8054 [4-((9-chloro-7-(2,6-difluorophenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)benzoic acid] is an orally available small-molecule reversible, ATP competitive inhibitor of recombinant Aurora A kinase (K_i = 7 nM). Additionally, MLN8054 displayed good selectivity against a panel of known kinases (IC₅₀ Aurora A = 31 nM) [1]. The activity of MLN8054 bound to the kinase domain of Aurora A has been reported to result in an unusual activation loop conformation, which may provide a basis for selectivity over Aurora B and other kinases that cannot adopt this conformation [1,2]. Studies have showen that in cultured cells such as HCT-116 MLN8054 selectively inhibits Aurora A over Aurora B at concentrations of about 1.0 uM, whereas a 4.0 uM concentration inhibits both Aurora A and B kinases [3].

The activity of MLN8054 is as follows:

IC₅₀ (Aurora A enzyme assay) = 31 nM; K_i = 7 nM

Common Name: MLN8054

Synonyms:  MLN8054; MLN-8054; MLN 8054

IUPAC Name: 4-((9-chloro-7-(2,6-difluorophenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)amino)benzoic acid

CAS Number: 869363-13-3

SMILES: C1C2=CN=C(N=C2C3=C(C=C(C=C3)Cl)C(=N1)C4=C(C=CC=C4F)F)NC5=CC=C(C=C5)C(=O)O

Mechanism of Action: Kinase Inhibitor; Aurora A Kinase Inhibitor

Indication: Various Cancers; Melanomas

Development Stage: Phase I

Company: Takeda Pharma

Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle, as its perturbation causes defects in centrosome separation, spindle pole organization, and chromosome congression.

It is suggested that Aurora A disruption leads to cell death via a mechanism that involves aneuploidy generation. However, the link between the immediate functional consequences of Aurora A inhibition and the development of aneuploidy is not clearly defined. In a reported study, authors have reproduced the sequence of events that lead to aneuploidy following Aurora A inhibition using MLN8054, a selective Aurora A small-molecule inhibitor. Human tumor cells treated with MLN8054 show a high incidence of abnormal mitotic spindles, often with unseparated centrosomes. Although these spindle defects result in mitotic delays, cells ultimately divide at a frequency near that of untreated cells. Reserachers that many of the spindles in the dividing cells are bipolar, although they lack centrosomes at one or more spindle poles. MLN8054-treated cells frequently show alignment defects during metaphase, lagging chromosomes in anaphase, and chromatin bridges during telophase. Consistent with the chromosome segregation defects, cells treated with MLN8054 develop aneuploidy over time. Taken together, these results suggest that Aurora A inhibition kills tumor cells through the development of deleterious aneuploidy [4].

References:

1. Sells, T. B.; et. al. MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors. ACS Med Chem Lett 2015, 6, 630-634.

2. Dodson, C. A.; et. al. Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design. Biochem J 2010, 427(1), 19-28.

3. Huck, J. J.; et. al. MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells both in vitro and in vivo. Mol Cancer Res 2010, 8(3), 373-384.
4. Hoar, K.; et. al. MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol 2007, 27(12), 4513-4525.

Drugs in Clinical Pipeline: AKI-001

AKI-001 [8-ethyl-3,10,10-trimethyl-4,5,6,6a,8,10-hexahydropyrazolo[4',3':6,7] cyclohepta[1,2-b]pyrrolo[2,3-f]indol-9(3aH)-one] a pentacycle represents a new class of pan-Aurora kinase inhibitors (IC₅₀ AURKA, AURKB = 0.004, 0.005 uM) with excellent oral availability and high potency against tumor xenografts in mouse. These properties compare favorably with those of other reported Aurora kinase inhibitors. Cellular studies support Aurora kinase inhibition (IC₅₀ HCT116, HT29, MCF7 = 0.070, 0.070, 0.10 uM) as the mechanism of antiproliferative activity and, presumably, of tumor growth inhibition [1].

Researchers assayed AKI-001 in a panel of kinase assays. Importantly, there is little inhibition of non-Aurora kinases important for cell cycle progression (for example, IC₅₀ CDK2, CHK1 = 15, 0.085 uM). However, AKI-001 does show off-target activities, most notably against receptor tyrosine kinases and Src family members as has been reported for other Aurora kinase inhibitors (IC₅₀ SRC, FLT3, KDR = 0.25, 0.002, 0.012 uM).

The activity of AKI-001 is as follows:

IC₅₀ (AURKA enzyme assay) = 0.004 uM

IC₅₀ (AURKB enzyme assay) = 0.005 uM

Common Name: AKI-001

Synonyms:  AKI-001; AKI 001; AKI001

IUPAC Name: N 8-ethyl-3,10,10-trimethyl-4,5,6,6a,8,10-hexahydropyrazolo[4',3':6,7] cyclohepta[1,2-b]pyrrolo[2,3-f]indol-9(3aH)-one

CAS Number: 925218-37-7

SMILES: -

Mechanism of Action: Kinase Inhibitor; pan-Aurora Inhibitor

Indication: Various Cancers; Anti-tumor Therapy

Development Stage: Investigational

Company: Genentech/Roche

Eidogen Sertanty Inc Provides Kinase Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.

Aurora kinases are a family of mitotic serine/threonine kinases conserved from yeast to humans, and they have received significant recent attention as new targets for anticancer therapy. The two major Aurora kinases, Aurora A and Aurora B, have distinct functions in mitosis. The third Aurora kinase, Aurora C, has a kinase domain most similar in sequence to that of Aurora B,and Aurora C appears to have functions that overlap with those of Aurora B.

Despite uncertainty surrounding the role of Aurora kinases in tumorigenesis, it is clear that both Aurora A and Aurora B are critical for completion of mitosis and for accurate cell cycle progression. As such, drugs targeting these kinases might be expected to have potent antimitotic and antitumor activity [1].

AKI-001 showed excellent antiproliferative activity against several tumor cell lines. This antiproliferative effect coincided with the compound concentration required to produce a G2/M block (24 h assay), as measured by flow cytometry. Researchers used several more specific cellular assays to judge whether the observed antiproliferative effect was driven by inhibition of Aurora A, Aurora B, or both. Overall, AKI-001  is approximately equipotent in cellular inhibition of Aurora A and Aurora B (consistent with the equivalent enzymatic IC₅₀ values), and the compound concentrations required to produce these effects are fairly close to the antiproliferative IC₅₀ values. This suggests that the antiproliferative effect is likely to be a consequence of Aurora inhibition [1].

References:
1. Rawson, T. E.; et. al. A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability. J Med Chem 2008, 51(15), 4465-4475.

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 (K_d A/B/C = 3/2/1 nM) as well as interactions (K_d 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; K_d = 3 nM

IC₅₀ (AURKB enzyme assay) = 4 nM; K_d = 2 nM

IC₅₀ (AURKC enzyme assay) = 1 nM; K_d = 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].

References:

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. ClinicalTrials.gov A Phase 1 First-in-Human Study Evaluating AMG 900 in Advanced Solid Tumors. NCT00858377 (retrieved on 22-04-2015)