The Shionogi BACE1 aspartyl protease inhibitor, atabecestat (JNJ-54861911) is an oral, brain-penetrant compound that was advanced into the EARLY Ph. IIb/III clinical trial for treatment of preclinical Alzheimer’s disease (AD) patients. The starting point was identified from a phenotypic HTS, and was the first thiazine-based BACE1 disclosed [...]

10. The Haisco voltage-gated calcium channel (VGCC) alpha-2-delta subunit inhibitor, HSK16149, is a potent and potentially longer-acting gabapentinoid drug candidate for chronic pain over pregabalin, with a potentially wider therapeutic index for the central nervous system (CNS). The molecule is planned for a Ph. II/III trial in China for [...]

11. The EMD Serono/Merck KGaA toll-like receptors TLR7/TLR8 inhibitor M5049 is an oral, twice-daily anti-inflammatory agent currently in a Ph. I trial for Lupus. The molecule potently blocks both synthetic ligands and natural endogenous RNA ligands such as microRNA and Alu RNA. TLR7 and TLR8 selective modulators (both agonists and [...]

12. The 2nd generation Constellation EZH2 histone methyltransferase inhibitor, CPI-1328, is an extremely potent tool compound with reversible femtomolar activity against EZH2, and is one of the most potent reversible small inhibitors ever reported. Previous analyses have suggested an empirical barrier for non-covalent inhibitors around 10 pM. [...]

13. The Yale BRAF-targeting PROTAC SJF-0628 is a VHL-based heterobifunctional degrader with in vivo activity in a xenograft model (50 mg/kg BID IP). Though mutant BRAF is a well-validated target, drugging mutant forms selectively over wild-type continues to be a challenge. It had been hypothesized that modalities such as targeted degradation [...]

14. The Novartis pan-serotype dengue virus (DENV) NS4B protein inhibitor, NITD-688, is a preclinical candidate with strong activity against all four serotypes of DENV in vitro and excellent oral efficacy in a mouse model. The starting point was identified through phenotypic screening of 1.5M compounds and counterselection against host factors [...]

1.The Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist (LSN3318839) is a positive allosteric modulator intended to treat type 2 diabetes. This drug candidate has an interesting proposed mechanism as a molecular glue between GLP-1R and GLP peptide, enhancing endogenous peptide activity. The starting point was identified from a 220k [...]

The November edition of Small Molecules of the Month includes two oral SARS-CoV-2 antivirals which may play an important role in life with endemic Covid, a remarkably selective CDK7 kinase inhibitor (>4000x), and a recently approved, once-daily MET inhibitor. If you find this series helpful, keep a close eye on drughunter.com in the coming days to catch what the team’s been working on for you behind the scenes…...

In Aug. 2021, immuno-oncology company, Trillium Therapeutics, was acquired by Pfizer for $2.3 billion , adding Trillium’s two CD47-targeting biologics, TTI-621 and TTI-622, to Pfizer’s oncology pipeline. The acquisition followed Gilead’s $4.9B buyout of Forty Seven in early 2020, after clinical data was presented on Forty Seven’s lead, the [...]

The GSK RIPK2 PROTAC, “compound 20”, demonstrates in vivo degradation of RIPK2 over 60 days after a single compound dose when administered SC in slow-release PLGA microparticles. This degrader was previously highlighted as a Molecule of the Month, voted by our readers as a final contender for Molecule of the Year in 2020 thanks to its [...]

The Bayer DNA-PK inhibitor, BAY-8400 , is an orally active and selective DNA-PK kinase inhibitor that synergistically enhances the efficacy of radiotherapeutics in xenograft models. The program started with a campaign to identify ATR inhibitors, which resulted in hits against ATR, ATM, and DNA-PK, all of which are of interest due to their [...]

The Xenon NaV1.6 Inhibitor, NBI-921352 , is remarkably selective for the NaV1.6 sodium channel over other isoforms (IC50 = 51 nM, 756x vs. NaV1.1, 134X vs. NaV1.2, 276X vs. NaV1.7, >583X vs. 1.3, 1.4, 1.5). The molecule is It is being developed to treat pediatric patients with SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) and [...]

The Takeda covalent BTK inhibitor clinical candidate, TAK-020 , is a highly selective oral covalent BTK inhibitor with safety and tolerability profiles that are promising for both hematologic malignancies and autoimmune diseases based on a study in healthy volunteers. The molecule originated from a simple triazolone fragment, and overall is a [...]

The AstraZeneca oral RORgt inverse agonist, AZD0284 , is an inverse agonist of the nuclear receptor RORC2 (RORγt). Reviewer Chris Gampe says, “targeting the activation and function of Th17 cells has been successful for the treatment of autoimmune disease (cf. IL-17, IL-17R, IL-23 Abs). RORC2 is the transcription factor that controls Th17 [...]

The Merck KGaA MCT4 chemical probe, “compound 18n” , is a novel inhibitor of the monocarboxylate transporter MCT4. Large quantities of lactic acid need to be transported out of tumor cells due to their dependence on glucose metabolism, and this transport is mediated by MCTs. Overexpression of MCT4 is a marker for poor prognosis in cancer, and [...]

The Biocryst oral plasma kallikrein inhibitor, berotralstat (BCX7353) , was recently approved as the first non-steroidal treatment for prevention of hereditary angioedema attacks. The molecule is given orally (150 mg QD) despite having two basic amines (dibasic). Interestingly for a chronically administered drug, the molecule is noted to have [...]

The Celgene/BMS PKCθ kinase inhibitor, CC-90005 , highlighted by Julien Lefranc , is a clinical candidate in Ph. I for psoriasis, with some dosing being conducted in healthy volunteers. The safety profile is impressive given how fraught with selectivity issues previous PKC inhibitors have been. The molecule is >550-fold selective for PKCθ [...]

The Astex ERK1/2 kinase inhibitor, ASTX029 , is an oral Ph. I-II candidate for patients with advanced solid tumors. The molecule was derived from fragment screening together with structure-based design. Interestingly, the molecule also blocks the phosphorylation/activation of ERK1/2 in addition to inhibiting its kinase activity, making it [...]