Discovery of 1‑(1<i>H</i>‑Pyrazolo[4,3‑<i>c</i>]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers

The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1<i>H</i>-pyrazolo­[4,3-<i>c</i>]­pyridin-6-yl)­ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound <b>21</b> exhibited potent target engagement and strong tumor regression in the BRAF^V600E xenograft model

Discovery of 1‑(1<i>H</i>‑Pyrazolo[4,3‑<i>c</i>]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers

The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1<i>H</i>-pyrazolo­[4,3-<i>c</i>]­pyridin-6-yl)­ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound <b>21</b> exhibited potent target engagement and strong tumor regression in the BRAF^V600E xenograft model

Discovery of 5‑Amino‑<i>N</i>‑(1<i>H</i>‑pyrazol-4-yl)pyrazolo[1,5‑<i>a</i>]pyrimidine-3-carboxamide Inhibitors of IRAK4

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-<i>N</i>-(1<i>H</i>-pyrazol-4-yl)­pyrazolo­[1,5-<i>a</i>]­pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing

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 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

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