Effect of MRLB-11055 on major lymphoid populations in spleen of WT B6 mice.

<p>MRLB-11055 was given for either 3 or 6 days (on), followed up by either a 0 or 4 day holiday (off), for up to 4 cycles. Effects on NK, B and T cells were measured by flow cytometry.</p

Discovery of 1‑[3-(1-Methyl‑1<i>H</i>‑pyrazol-4-yl)-5-oxo‑5<i>H</i>‑benzo[4,5]cyclohepta[1,2‑<i>b</i>]pyridin-7-yl]‑<i>N</i>‑(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c‑Met/Ron Dual Kinase Inhibitor with Preferential Affinity for the Activated State of c‑Met

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5<i>H</i>-benzo­[4,5]­cyclohepta­[1,2-<i>b</i>]­pyridin-5-one <b>11r</b> (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of <b>11r</b> was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access <b>11r</b> and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, <b>11r</b> provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase conformation

Exposure and target engagement of MRLB-11055 in the peripheral blood of C57BL/6 mice stimulated with darbepoetin.

<p>A. Effect of MRLB-11055 on phosphoSTAT5 levels at various times post-dose. B. Calculation of IC50 value for inhibition of phosphoSTAT5. C. PK of 3 doses of MRLB-11055 in mouse blood, with calculated IC50 superimposed (dashed line).</p

Effect of 2 Cycles of Intermittent Dosing (3 days on, 4 days off) of MRLB-11055 on V617F-Luc2 Mice (N = 10).

<p>Effect on A & B. Bioluminescence in spleen C. Hematocrit D. Multiple endpoints at end of study (Day 14).</p

Effect of MRLB-11055 in a Darbepoetin-Induced PV Efficacy Model.

<p>The ability of MRLB-11055 to prevent darbepoetin-induced increases in hematocrit (Hct) and spleen mass (SPL) over 7 days is shown, as is the impact of MRLB-11055 on white blood cells (WBC) and its concentration in blood (PK). Dashed line indicates <i>in vivo</i> IC50 value.</p