CPI-1612 is a pretty efficient-looking EP300/CBP histone acetyltransferase (HAT) inhibitor tool compound with demonstrated activity in a xenograft model and good higher species PK. While epigenetics targets like HATs have been hot this decade, many programs have run into tolerability challenges and/or difficulty identifying activity [...]

“Compound 19” is a JAK1/TYK2 dual kinase inhibitor from Pfizer, related to its clinical JAK1/TYK2 dual inhibitor, brepocitinib, in Ph. II for a variety of inflammatory diseases. The cyclopropyl amide group was designed to displace a high energy water molecule. It was probably fortunate for their manufacturing colleagues that brepocitinib was [...]

AZD4205 is a JAK1-selective kinase inhibitor which is in clinical development for oncology rather than the inflammatory diseases most JAK1 inhibitors have aimed for. The compound has excellent PK in dog, and the authors demonstrate that JAK1 inhibition doesn’t have strong single-agent activity in a xenograft model but can synergize [...]

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with activity against both serine and zinc metallo-beta-lactamases, in contrast to approved beta-lactamase inhibitors such as relebactam which are only active against serine metalloproteases. Interestingly, the boron of the molecule coordinates to serine hydroxyl groups in serine [...]

“Compound 9” is the first potent M3-selective positive allosteric modulator, with potential utility as a biological tool compound. It does have secondary activity against M5 at high doses though. It’s quite a large zwitterion, which is somewhat unusual for GPCRs.

“Compound ( P )-14″ is a PI3K beta-isoform selective lipid kinase inhibitor. While the compound is potent and has excellent oral PK in higher species, significant irreversible toxicity was observed in a tox. study, and the chemical series was discontinued. It’s always great when organizations disclose tox. findings to educate the community [...]

FT385 is a covalent inhibitor of the USP30 deubiquitinating enzyme with a cyanopyrrolidine warhead. Identifying selective active-site inhibitors of de-ubiquitinating enzymes has been challenging, and FT385 now provides a good tool compound to study USP30 biology. Some of my colleagues at Genentech recently published on the mechanism of [...]

CC-92480 (Celgene/Bristol Myers Squibb (BMS) oral in vivo CRBN-based selective IKZF1/3 degrader)

“PROTAC 6” (GlaxoSmithKline (GSK) IAP-based selective RIPK2 degrader with prolonged in vivo PD)

GSK620 (GlaxoSmithKline (GSK) oral in vivo BD2 domain selective BET inhibitor)

Merck hArg1 inhibitor (Merck oral in vivo human arginase 1 inhibitor) DHMOTM2020-03-04

Merck IDO1 inhibitor (Merck heme-displacing oral IDO1 inhibitor)

Constellation EZH2 inhibitor (Constellation oral in vivo long-residence time EZH2 inhibitor)

Arcus CD73 inhibitor (Arcus non-nucleoside CD73 inhibitor)

MK-6884 (Merck M4 positive allosteric modulator PET tracer) 2022 Update: Human Ph. I data disclosed in https://doi.org/10.1126/scitranslmed.abg3684

Sulfopin (Weizmann/Harvard selective covalent Pin1 inhibitor)

M3814 (Merck KGaA oral DNA-PK selective kinase inhibitor)

Remibrutinib (Novartis oral BTK-selective covalent kinase inhibitor clinical candidate)