Monday, May 25, 2015

Drugs in Clinical Pipeline: AC710

AC710 [N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-5-((1-ethyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy)picolinamide] is a potent, selective PDGFR-family kinases inhibitor with IC50 of 7.7 nM against PDGFRβ. AC710 has the Kd values of 0.6 nM/1.0 nM/1.3 nM/1.0 nM for FLT3/KIT/PDGFRα/PDGFRβ respectively.

AC710 was very selective across the entire panel of 386 unique kinases as demonstrated by the very low S(10) scores and more than 30-fold selectivity over any other non-PDGFR kinases. Secondly, AC710 has very similar binding affinities for the PDGFR-family kinases. FLT3 appeared to be the target that was more potently inhibited by AC710. Moreover, KIT, PDGFR, and CSF1R were equally inhibited by AC710, with slightly more potency in inhibiting KIT phosphorylation. AC710 also showed clean cytochrome P450 inhibition profiles (IC50 values > 40 µM) against a panel of five isoforms (1A2, 2C9, 2C19, 2D6, and 3A4). No Cyp induction was observed for AC710 when tested at 3 and 30 µM concentrations against three isoforms (1A2, 2D6, and 3A4) [1].

The activity of AC710 is as follows:

IC50 (CSF1R enzyme assay) = 10.5 nM
IC50 (FLT3 in MV4-11 cells) = 2 nM; Kd = 0.6 nM
IC50 (KIT in H526 cells) = 1.2 nM; Kd = 1.0 nM
IC50 (PDGFRβ enzyme assay) = 7.7 nM

Common Name: AC710
Synonyms:  AC710; AC 710; AC-710
IUPAC Name: N-(4-(3-(5-(tert-butyl)isoxazol-3-yl)ureido)phenyl)-5-((1-ethyl-2,2,6,6-tetramethylpiperidin-4-yl)oxy)picolinamide
CAS Number: 1351522-04-7; 1351522-05-8 (mesylate)
Mechanism of Action: Kinase Inhibitor; PFKFB3 Inhibitor
Indication: Various Cancers; Inflammatory Arthritis
Development Stage: Investigational
Company: Ambit Biosciences

Novel small molecule inhibitors targeting both FLT3 and CSF1R can be developed for either FLT3-ITD+ AML or cancer bone metastasis and rheumatoid arthritis. Synergy can also potentially be realized for autoimmune diseases by inhibiting both FLT3 and CSF1R simultaneously. A number of dual FLT3 and CSF1R inhibitors are being studied in clinical settings.

The antitumor efficacy of AC710 was assessed in a subcutaneous flank-tumor xenograft model in athymic nude mice using the MV4-11cell line, a human leukemia cell line that is FLT3-dependent and harbors a homozygous FLT3-ITD mutation. AC710 was dosed at 0.3, 3, and 30 mg/kg for 2 weeks. At 0.3 mg/kg of AC710, tumor growth was temporally inhibited, and growth resumed quickly thereafter. At 3 and 30 mg/kg of AC710, tumors regressed completely, and the tumor volume stayed suppressed for an extended period after dosing was halted. No body weight loss was observed in animals treated with AC710 at all doses, indicating that it is well tolerated in mice at efficacious doses [1].

AC710 was further evaluated prophylactically in a mouse collagen-induced arthritis (CIA) model. AC710 exhibited a significant impact on disease in a dose-dependent fashion, at a dose as low as 3 mg/kg for 15 days (day 0-14) as measured by paw clinical scores. At 10 and 30 mg/kg, AC710 demonstrated equivalent or slightly better efficacy in reducing the joint swelling and inflammation than dexomethasone administered at a safe dose [1].

1. Liu, G.; et. al. Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases. ACS Med Chem Lett 2012, 3(12), 997-1002.