| Description: |
IRE1 RNase inhibitor 8866(MKC8866) is an inositol requiring enzyme 1 (IRE-1α) inhibitor with an IC50 of less than 0.1 μM. |
| Target: |
IC50: <0.1 μM (IRE-1α)[1] |
| In Vivo: |
MKC8866 is a selective IRE1 RNase inhibitor that exhibits acceptable pharmacokinetic and toxicity profiles. To determine the efficacy of MKC8866 treatment in vivo, MDA-MB-231 tumor xenografts are established in athymic nude mice. Once tumors have reached a palpable size (225-250 mm3), animals are randomized into treatment groups and treated with vehicle alone, 300 mg/kg MKC8866 alone, 10 mg/kg Paclitaxel alone or a combination of Paclitaxel and MKC8866. Treatments in all groups are administered until tumors reach maximal size (2000 mm3) or on day 60, whichever came first. MKC8866 is well tolerated after 60 consecutive oral doses and, based on pharmacokinetic allometric scaling, systemic exposures are well above anticipated clinical therapeutic levels. Following MDA-MB-231 tumor formation, mice are treated with Paclitaxel alone (7.5 mg/kg) for days 1-10, or a combination of Paclitaxel (days 1-10) and MKC8866 (300 mg/kg, days 1-28). After withdrawal of Paclitaxel treatment on day 10, an initial reduction in tumor volume is apparent in both treatment groups. Tumor re-growth, evident after day 18 in those animals receiving no further treatment, is repressed in the treatment group still receiving MKC8866. Tumor re-growth is only apparent in this group following cessation of MKC8866 on day 28[2]. |
| In Vitro: |
Protein folding stress in the endoplasmic reticulum of a cell initiates a signal transduction cascade termed the unfolded protein response or UPR. A key enzyme, inositol requiring enzyme 1 (IRE-1α), relieves protein folding stress by enhancing molecular chaperone activity and therefore protects cells from stress induced apoptosis. MKC8866 is useful for treating at least B cell autoimmune diseases, certain cancers, and some viral infections. MKC8866 (Compound 167) inhibits IRE-1α in the in vitro assay with an IC50 of <0.1 μM. MKC8866 (Compound 167) IRE-1α in an in vivo XBP-1 splicing assay (e.g., in myeloma cells) with an EC50<10 μM[1]. |
| Animal Administration: |
Mice[2] For the xenograft regrowth post-Paclitaxel in vivo experiments, female athymic nude mice (Crl:NU(Ncr)-Foxn1nu) are implanted subcutaneously in the right flank. Following establishment of palpable tumors, mice are randomized into treatment groups consisting of 10 mice per group with group mean tumor volumes from 227 to 230 mm3 (considered day 1 of treatment). A 7.5 mg/mL Paclitaxel stock solution in 50% ethanol: 50% Cremophor EL is prepared and stored at room temperature protected from light prior to dosing. On each day of dosing, an aliquot of the Paclitaxel stock is diluted with 5% dextrose in water (D5W) to yield a 0.75 mg/mL Paclitaxel dosing solution in a vehicle consisting of 5% ethanol: 5% Cremophor EL: 90% D5W (Vehicle 1) which provides the 7.5 mg/kg dose in a 7.5 mL/kg dosing volume. Mice are administered 7.5 mg/kg Paclitaxel once every other day for five doses by intravenous injection. MKC8866 is administered daily for 28 days at a dose volume of 10 mL/kg from a 30 mg/mL suspension in 1% microcrystalline cellulose in a simple sugar at 300 mg/kg daily by oral gavage (Vehicle 2). Group 1 receive Paclitaxel (7.5 mg/kg) alone while Group 2 receive Paclitaxel (7.5 mg/kg) plus 300 mg/kg MKC8866[2]. |
| References: |
[1]. Zeng, Qingping, et al. IRE-1α inhibitors. US9867803.
[2]. Logue SE, et al. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat Commun. 2018 Aug 15;9(1):3267. |
