Monday, September 28, 2015

Drugs in Clinical Pipeline: AC410

AC410 [(S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol] is a potent, selective, orally-administered, small molecule inhibitor of Janus kinase 2 (JAK2, Kd = 0.18 nM) and has potential utility in autoimmune and inflammatory indications. JAK2 mediates the signaling of specific cytokines, including IL-5, IL-6, IL-12, IL-13, IL-23, and GM-CSF; each cytokine has a specific role for the immune system. The specific and potent inhibition of these cytokines could provide a more powerful impact on diseases than a bulk inhibition of JAK family members. The specificity of AC410 for JAK2 vis-a-vis JAK1 (Kd = 2.5 nM) and JAK3 (Kd = 5 nM) gives Ambit (Now Daichii Sankyo) an opportunity within the existing market landscape [1].

Ambit’s initial JAK2 candidate was AC430 [(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol], a racemic mixture of two enantiomers, AC410 and AC409 [(R)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol]. Ambit has chosen AC410 for further clinical development based on superior pharmacokinetics and potent anti-inflammatory properties in a preclinical model, and its inhibitory activity of JAK2 in cellular assays.

JAK2 is a member of the Janus kinase family, which includes JAK1, 2, 3, and Tyk2. Each member of the family mediates the signaling of a distinct set of cytokines that are involved in activation, proliferation, and survival of immune cells. Improper activation of cytokines can induce and exacerbate inflammation within the body and lead to inflammatory diseases.

The activity of AC410 is as follows:

Kd (JAK1 binding assay) = 2.5 nM
Kd (JAK2 binding assay) = 0.18 nM
Kd (JAK3 binding assay) = 5 nM
Kd (TYK2 binding assay) = 1.6 nM

The activity of AC430/AC409 is as follows:

Kd (JAK1 binding assay) = 6/15 nM
Kd (JAK2 binding assay) = 0.3/0.5 nM
Kd (JAK3 binding assay) = 10.5/21 nM
Kd (TYK2 binding assay) = 1.8/8.8 nM

Common Name: AC410
Synonyms: AC410; AC 410; AC-410
IUPAC Name: (S)-(4-fluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)methanol
CAS Number: 
Mechanism of Action: Kinase Inhibitor; JAK2 Inhibitor
Indication: Various Cancers; Anti-inflammatory Agents; Treatment of Autoimmune diseases
Development Stage: Phase I
Company: Ambit Biosciences: Daiichi Sankyo

The JAK kinase family is a cytoplasmic protein kinase family comprising the members JAK1, JAK2, JAK3, and TYK2. They all share a similar structure characterized by the presence of seven JAK homology (JH) domains. JAK1, JAK2 and TYK2 are expressed ubiquitously in mammals, whereas JAK3 expression is limited mainly to haematopoietically derived cells. As such, JAK3 is important for leucocyte activation and proliferation; namely, natural killer (NK), T and B cells.

Growth factor or cytokine receptors that recruit JAK kinases include the interferon receptors, interleukin receptors (receptors for the cytokines IL-2 to IL-7, IL-9 to IL-13, IL-15, IL-23), various hormone receptors (erythropoietin (Epo) receptor, the thrombopoietin (Tpo) receptor, the leptin receptor, the insulin receptor, the prolactin (PRL) receptor, the granulocyte colony-stimulating factor (G- CSF) receptor, the growth hormone receptor, receptor protein tyrosine kinases (such as EGFR and PDGFR), and receptors for other growth factors (leukemia inhibitory factor (LIF), oncostatin M (OSM), IFNα/ß/γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1)). JAK1 and JAK3 are responsible for the signal transduction of cytokine receptors containing the IL-2 receptor common γ chain, thus mediating signalling by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokines that are essential for the development and maturation of T lymphocytes. Conversely, JAK2 is associated with haematopoietic growth factor receptors, as well as gp40-containing cytokine receptors. 

1. Holladay, M. W.; et. al. An optically active pyrazolylaminoquinazoline, and pharmaceutical compositions and methods of use thereof. WO2012030917A1