EC2629 is a folate receptor (FR)-targeted small molecule drug conjugate with a folate receptor-targeting moiety, a pyrrolobenzodiazepine (PBD) DNA-crosslinking warhead, and a linker. Similar to antibody-drug conjugates, this small molecule conjugate is intended to maintain the activity of the potent PBD warhead while minimizing systemic [...]

BAY 1003803 is a potent topical agonist of the glucocorticoid receptor (GR) transrepression pathway, with less activity on the GR transactivation pathway mediated by GR dimers, which may lead to undesirable side effects. The fluoroaminoquinoline was the only heterocycle among analogs tested that was Ames-negative. The compound appears to have [...]

GS-9688 (selgantolimod) is a potent and selective TLR8 agonist sparing related receptor TLR7, and is intended to induce better immune responses in chronic hepatitis B. Since systemic activation of TLR8 was undesirable, selgantolimod was designed to have high first-pass hepatic clearance to induce effective antiviral immunity in the liver but [...]

JTE-052 (delgocitinib) is a pan-JAK kinase inhibitor approved as a topical ointment for treatment of atopic dermatitis in Japan. The compound has an interesting azetidine-containing diazaspirocycle core and a relatively high sp3-fraction for a kinase inhibitor.

“Compound 10” is a potent and selective inhibitor of Class I histone deacetylases (HDAC1/2/3) which increases HIV activity in treatment-suppressed patient immune cells for the goal of eradicating HIV from latent reservoirs. Fascinatingly, the compound 10 actually binds to a zinc ion in the HDAC proteins through a ketone hydrate, formed in [...]

BAY 1895344 is a potent and highly selective inhibitor of the ATR kinase, which is involved in the DNA damage response. Further disruption of the DNA damage response via ATR inhibition is expected to induce synthetic lethality in cancers with already impaired DNA damage repair mechanisms. The Bayer team was able to overcome poor solubility in [...]

JNJ-53718678 is a potent and orally available fusion inhibitor of the RSV virus, optimized from a prior oral inhibitor, BMS-433771. The prior inhibitor was challenged by moderate potency, suboptimal PK in preclinical species, limited lung distribution, and potential complications from CYP TDI due to an aminocyclopropyl moiety. The improved [...]

“Compound 19” (iron-binder) is an oral inhibitor of the hypoxia-inducible factor (HIF) propyl hydroxylase domain (HIF-PHD), increasing HIF levels to activate EPO transcription and promote hematopoiesis for treatment of anemia. Interestingly, this compound is modeled to make a bi-dentate interaction with an iron co-factor of HIF-PHD via a [...]

“Compound 2” binds to a lipid pocket on TEAD transcription factors, transforming TEAD from a transcriptional co-activator to a dominant-negative transcriptional repressor of Hippo pathway signaling. The tool molecule demonstrates activity against xenograft models, and will be useful for understanding Hippo pathway biology.

“Compound 19” is a selective brain-penetrant inhibitor of the ceramide galactosyltransferase UGT8, intended for use in substrate reduction therapy for rare lysosomal storage disorders. The compound has good oral exposure in higher species (%F = 52 in dog) and is active in models looking at enzymatic activity using isotopically-labeled [...]

BI-0115 inhibits the C-type lectin family member lectin-like oxidized LDL-receptor-1 (LOX-1) by stabilizing an inactive tetrameric form of the protein. Interestingly, co-crystollography demonstrates that inter-ligand interactions between two BI-0115 molecules contribute to the dimerization of LOX-1 homodimers.

ASP5286 is an analog of the natural product cyclosporin A that maintains the anti-HCV activity of cyclosporin A by binding to cyclophilin, but was optimized to be less immunosuppresive than cyclosporin A. The macrocycle was identified through semisynthetic derivitization of a related natural product, FR901459. The Astellas team was able to [...]

( R )-CR8 is a known CDK inhibitor that was recently discovered to be a molecular glue-type degrader of cyclin K. A crystal structure of an E3 component-CR8-CDK12-cyclin K complex shows that CR8 acts by binding to the active site of a CDK (which binds to cyclin K), and recruiting an E3 component through a solvent-exposed lipophilic moiety on [...]

MK-5204 is a broad spectrum Candida antifungal agent derived from the natural product, enfumafungin. I was impressed that the molecule not only demonstrates oral efficacy but also has good oral PK in higher species (dog, cyno), given that the molecule is a large zwitterion with several very polar groups, including a primary amide, primary [...]

“Compound 6f” is a potent macrocyclic factor XIa inhibitor (<1 nM) that is highly selective against other serine proteases and has excellent oral PK (high bioavailability, low clearance). The BMS team was able to troubleshoot metabolic instability through met. ID, which revealed a hotspot outside of the macrocycle.

“Compound 34” is a mechanism-based inhibitor of lysine-specific demethylase LSD1 (aka KDM1A). LSD1 has an FAD co-factor which is covalently modified by the cyclopropylamine in compound 34 likely through an electron-transfer mechanism (as for tranylcypromine and MAOs). Interestingly, the 4,4-spiro amine provided an improvement to in vitro [...]

GNE-149 is an efficient monovalent degrader and full antagonist of estrogen receptor alpha with significant oral bioavailability in higher species. The standard-of-care selective ER degrader (SERD) fulvestrant is not orally bioavailable and is believed to achieve incomplete target occupancy in humans. The full antagonist profile of GNE-149 is [...]

[18F]LSN3316612 is a PET radiotracer for quantifying levels of O-GlcNAc hydrolase (OGA) in the brain. OGA is an enzyme involved in the post-translational modification of tau protein, and OGA may be a useful biomarker for neurodegenerative disease drug development. The fluorine radiolabel was introduced through nucleophilic aromatic [...]