| Description: |
AZD7507 is a potent and orally active CSF-1R inhibitor, with antitumor activity. |
| Target: |
CSF-1R[1] |
| In Vivo: |
AZD7507 has good rat oral PK, with in vivo clearance of 7 mL/min/kg and 42% bioavailability. In the canine L-type Ca channel assay, the IC50 is >20 μM[1]. AZD7507 significantly decreases the number of CD68+ macrophages in mice, and also reduces the volume and mass in mice bearing CC-LP-1 and SNU-1079 cells, but not WITT-1 cells[2]. |
| In Vitro: |
AZD7507 (Compound 31) inhibits the proliferation of 3T3 cells engineered to express CSF-1R and stimulated with CSF-1 (IC50, 32 nM), shows inhibitory activity against hERG and NaV1.5, with IC50s of >30 and 26 μM[1]. |
| Animal Administration: |
Mice[2] Male CD1 nude mice are injected subcutaneously with 5 × 105 human ICC cells from human cell line WITT-1, CC-LP-1, or SNU-1079 (n = 24 in all cases) suspended in culture media/RGF Matrigel (Gibco) mix (1:1). Cells are engrafted bilaterally in the flank and allowed to form tumors over 3 weeks. Once palpable tumors have formed, mice are randomized into 3 groups using GraphPad online software. Xenografted mice are injected with liposomal clodronate at 4 μL/g intravenously. The control for this treatment is saline alone or liposomes not containing clodronate (both given at 4 μL/g intravenously). All of these treatments are given every 48 hours for 3 weeks. CSFR1 inhibitors AZD7507 and GW2580 are made up in sterile water containing 0.5% methylcellulose and 0.1% Tween-80. AZD7507 is given twice daily at 100 mg/kg, whereas GW2580 is given daily at 160 mg/kg. Control animals are given water containing 0.5% methylcellulose and 0.1% Tween-80. ICG-001 (5 mg/kg) or C-59 (20 mg/kg) is given by intraperitoneal injection. The vehicle for this is physiological saline. Control animals are given vehicle alone. In all cases inhibitors and vehicle are given 3 times per week[2]. |
| References: |
[1]. Scott DA, et al. Mitigation of cardiovascular toxicity in a series of CSF-1R inhibitors, and the identification of AZD7507. Bioorg Med Chem Lett. 2013 Aug 15;23(16):4591-6.
[2]. Boulter L, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. Send to J Clin Invest. 2015 Mar 2;125(3):1269-85. |
