AL-611 is a prodrug to a nucleoside inhibitor of HCV NS5B polymerase. While there have been very successful nucleoside drugs (e.g. sofosbuvir), several nucleoside inhibitors of HCV previously failed in the clinic due to severe toxicities, in some cases due to incorporation of the nucleosides into host RNA. The Janssen Biopharma (formerly [...]

PF-06882961 is an oral small molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists increase the production of insulin and are highly useful in the treatment of diabetes. However, until the recent introduction of an oral formulation of semaglutide, GLP-1 agonists were all peptides requiring inconvenient injections. [...]

PF-05221304 is a liver targeted inhibitor of acetyl-CoA carboxylase (ACC). ACC is a key regulator of lipid metabolism, and there has been significant interest in ACC inhibitors for the treatment of multiple indications including NASH and diabetes. Pfizer previously took a systemic ACC inhibitor into the clinic (PF-05175157), which was found [...]

PF-06835919 is an oral first-in-class clinical candidate for NAFLD/NASH targeting ketohexokinase (KHK), an enzyme which initiates the metabolism of fructose. The authors describe a very elegant structure-based design campaign to improve a modestly active, quickly cleared lead molecule into this highly potent, permeable, bioavailable, and [...]

“compound 9” is an investigational prodrug of pibrentasvir (ABT-530), a key component of AbbVie’s marketed HCV combination Mavyret. Pibrentasvir (PIB) is the largest approved oral small molecule since 1983 (MW = 1113, not including the peptide semaglutide at MW = 4113), and came with some solubility issues (aq. sol. pH 7 = <0.0001 mg/mL). The [...]

GLPG1205 is a potent, selective, and orally bioavailable negative allosteric modulator of the GPCR GPR84, a receptor associated with inflammation. Despite possessing both a dioxane ring and an relatively unhindered alkyne, the molecule has low clearance and is highly bioavailable in preclinical species (>100% F). The molecule was taken into a [...]

OP-5244 is a potent (250 pM), orally bioavailable inhibitor of the nucleotidase CD73, in contrast to the previously highlighted IV inhibitor in July . I thought it was remarkable that the ORIC team was able to identify an orally available, low clearance, and permeable compound with phosphonic acid motif and four other hydrogen bond donors [...]

SCO-267 is a full agonist of the GPCR GPR40, whose activation stimulates secretions of insulin and incretin. Since no crystal structures were available, the authors used conformational modeling to rationally improve the ligand from a weak lipophilic initial starting point (0.4 uM, clogP 9.4) to a more lipophilically efficient candidate (12 nM [...]

“compound 23” is a selective CRBN-based degrader of the pseudokinase, IRAK3, with in vitro activity in primary human cells. A volcano plot shows remarkable separation between IRAK3 degradation vs. most other proteins, with very little activity against family members IRAK1 and IRAK4. The authors were able to quickly generate this degrader from [...]

TAS-120 (futibatinib) is an orally available, irreversible FGFR1-4 inhibitor with a unique binding mode, targeting a unique cysteine in the P-loop of the FGFRs, rather than the Cys in the hinge region of FGFR4 as for roblitinib (above) or BLU9931 and fisogatinib. It is currently the most advanced irreversible FGFR inhibitor in clinical [...]

“compound 3d” is a prodrug which is phosphorylated in vivo to form a potent sphingosine-1-phopshate receptor modulator. BMS took two previous compounds into the clinic for MS with the goal of differentiating from fingolimod on safety. One potential issue for a previous compound was an overly long (12 day) half-life which could be undesirable [...]

GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is [...]

PF-06826647 is a TYK2-selective kinase inhibitor which binds to the catalytically active JH1 kinase domain, in contrast to BMS-986165, a TYK2 inhibitor in Ph. III for psoriasis that binds to the JH2 pseudokinase domain. TYK2-selective inhibitors are expected to have anti-inflammatory activity with reduced side effects such as anemia due to [...]

MSA-2 is an orally available agonist of the STING protein, which potently induces inflammation. Clinically evaluated cyclic dinucleotide-based STING agonists have typically been dosed intratumorally to promote anti-tumor inflammation but avoid systemic inflammation. The compound binds in a 2:1 stoichiometry with STING, and forcibly dimerized [...]

SR-717 is STING agonist with a surprisingly similar mechanism to MSA-2, published contemporaneously with MSA-2. The identification of a second carboxylic acid-type molecule with both 2:1 binding stoichiometry and apparent tumor selectivity support both papers’ MoA hypotheses.

Vixotrigine (BIIB074) is a voltage-gated sodium channel blocker that preferentially binds to the inactivated state of the sodium channels, conferring selectivity for channels involved in pain-associated high frequency nerve signalling over normal low frequency nerve signalling (use-/state-dependence). The use-dependent activity is believed to [...]

BI-3406 is a compound which binds to SOS1, preventing it from activating the oncoprotein KRAS. While inhibition of WT-KRAS and MEK alone are anticipated to be toxic, the combination of a SOS1 inhibitor with a MEK inhibitor appears to have a broader therapeutic index due to synergy in KRAS-driven tumors. A related undisclosed SOS1 inhibitor [...]

“compound 12” is a selective inhibitor of integrin αvβ5, a potential target for sepsis due to its potential role in regulating vascular leakage. Selectivity among integrin family members can be challenging to achieve and can have significant safety implications – hence, most integrin drugs have been selective biologics. Since the biological [...]