Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1

“…At the time of this work, no X-ray crystal structures of HPK1 had been published, and we had not yet been able to generate a construct of the protein that yielded crystals, either alone or bound to a ligand. − Instead, we relied on a homology model based on an X-ray crystal structure of the structurally related kinase, MST1 (PDB: 3COM; Figure ). Docking of compound 2 into that homology model suggested that the pyrimidine, the aniline NH, and the amide NH formed hydrogen bonds to the extended hinge region of HPK1, consistent with the binding of this chemotype to IRAK4 . Further examination of the homology model suggested the possibility of an intramolecular hydrogen bond between the amide oxygen and the phenylglycinol NH which may serve to orient the phenyl and hydroxymethyl substituents.…”

“…Mining of historical kinome selectivity data at Bristol Myers Squibb led to the identification of 1 (Figure 1), a compound prepared for our previously disclosed IRAK4 inhibitor program. 7 This compound demonstrated very promising potency in our caliper-based HPK1 inhibition assay (HPK1 IC 50 = 110 nM). When tested in a panel of >250 kinase assays, this compound demonstrated significant off-target kinase activity, inhibiting 25 kinases with an IC 50 less than 1 μM.…”

“…Mining of historical kinome selectivity data at Bristol Myers Squibb led to the identification of 1 (Figure ), a compound prepared for our previously disclosed IRAK4 inhibitor program . This compound demonstrated very promising potency in our caliper-based HPK1 inhibition assay (HPK1 IC 50 = 110 nM).…”

“…Docking of compound 2 into that homology model suggested that the pyrimidine, the aniline NH, and the amide NH formed hydrogen bonds to the extended hinge region of HPK1, consistent with the binding of this chemotype to IRAK4. 7 Further examination of the homology model suggested the possibility of an intramolecular hydrogen bond between the amide oxygen and the phenylglycinol NH which may serve to orient the phenyl and hydroxymethyl substituents. When so oriented, the hydroxy substituent is well-positioned to form a hydrogen bond with the side chain of Asp101.…”

Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis

“…We have previously reported the discovery of a series of small molecule IRAK4 inhibitors and identified ( 1 , Figure ) as a lead compound with excellent IRAK4 enzyme activity and moderate kinome selectivity (SI 33 of 9.7). However, 1 and the close analog 2 suffered from poor Caco-2 permeability preventing advancement to in vivo efficacy studies.…”