The Boehringer RORγ antagonist, BI 730357, is an oral once-daily clinical candidate from a new compound class in development for plaque psoriasis. We highlighted two other RORγ modulators last year in February and March. While most clinical RORγ modulators have discontinued development after reaching Ph. II, BI 730357’s Ph. II trial appears [...]

The Merck LRRK2 inhibitor, MLi-2, is an orally available tool compound that is structurally distinct from the LRRK2 inhibitor GNE-7915. LRRK2 had been a highly attractive target for treating Parkinson’s disease, but pulmonary toxicity observed with LRRK2 inhibition in non-human primates (NHP) cast a shadow on the utility of LRRK2 inhibitors [...]

The GSK αvβ6 integrin inhibitor, “compound 1,” or GSK 3008348 is a previously reported IPF clinical candidate that is a picomolar binder to αvβ6 with slow dissociation kinetics. The recent report highlights the fact that the compound results in prolonged effects in cells by triggering integrin internalization and lysosomal degradation. While [...]

The Takeda O-GlcNAcase (OGA) inhibitor, “compound 5i,” binds to the same site as prior sugar-based OGA inhibitors, but has surprisingly different chemical properties and a unique binding mode. The Takeda team realized that polar, sugar-based OGA inhibitors would be challenging to get into the brain where they would be needed for [...]

The Eisai β-catenin/CBP inhibitor, E7386, is an orally active and selective inhibitor of the β-catenin/CBP protein-protein interaction, a key node in the long studied Wnt/β-catenin pathway in cancer. Prior attempts to drug Wnt directly were met with severe toxicity in clinical trials. The pathway has seen a resurgence in interest due to its [...]

The Novartis BET bromodomain inhibitor, NVS-BET-1, is a new chemotype of BRD4 (BD1 and BD2) inhibitor. While we recently highlighted a few high-profile, selective bromodomain inhibitors from AbbVie and GSK, the Novartis team took a different approach to reaching their molecules. The Novartis team was looking for mechanisms that influence [...]

The BMS HIV-1 maturation inhibitor, “compound 16,” is a potent derivative of the clinical candidate GSK3532795/955176, with double-digit nanomolar activity in cells. The spiro[3.3]hept-5-ene effectively replaces a phenyl ring its parent molecule. Though it wasn’t taken beyond an in vitro assay, the structure is worth noting in the mental [...]

The academic covalent ALKi inhibitor, Con B-1, is thought-provoking initial proof-of-concept that remote kinase cysteines might be targetable from an active-site inhibitor. The authors show that a derivative of ceritinib with a remote electrophile attached can inhibit ceritinib more potently than a non-reactive control compound, that linker [...]

Novo oral insulin analog

Pfizer noncovalent oral hemoglobin (HbS) modulator

AstraZeneca oral reversible ERK1/2 kinase inhibitor

Pfizer oral PI3ka-selective kinase inhibitor prodrug

Taisho non-hydroxamate LpxC deacetylase inhibitor

AstraZeneca selective CDK9 kinase inhibitor

Bristol Myers Squibb (BMS) selective TNFα allosteric inhibitor

AbbVie selective TNFα allosteric inhibitor

Bristol Myers Squibb (BMS) oral JH2-domain binding Tyk2 kinase inhibitor

Beigene oral, brain-penetrant PARP1/2 inhibitor/DNA trapping agent