The drug discovery community kicked off the summer with a lot of very interesting molecules published in June. After ~50 molecular highlights so far this year, you’d think we’ve seen it all, but there were again numerous fascinating chemical motifs, molecular mechanisms, and biological observations disclosed last month. In this group are some natural-product inspired molecules, two metal-binding molecules (including a drug that binds its target via its ketone hydrate, something I had not seen before!), two transcription factor modulators, a molecular glue degrader, a receptor tetramerizer, and several clinical candidates. Links to the articles and more commentary below.

Small Molecules of the Month - June 2020

Subscribe to get a link to download a high-resolution PDF of June 2020's "Small Molecules of the Month."

send download link to:

I confirm that I have read and agree to the Terms of Use and Privacy Policy.

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 amine, carboxylic acid, and triazole. Development of this molecule was discontinued in favor of a further optimized analog, ibrexafungerp (MK-3118, SCY-078), currently in phase III clinical trials.

“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.

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 not systemic immunity. Though the molecule is weakly basic, in the low pH (~4-6) environment of the endosomal compartment, the weakly basic heterocycle is protonated, enabling it to make a favorable charged interaction with Asp543 in TLR8. Also interestingly, since the woodchuck hepatitis virus (WHV) is closely related to hepatitis B, a woodchuck model was used for preclinical experiments supporting clinical development.

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 situ from a ketone. Definitely a co-crystal structure worth taking a look at.

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 an initial lead to identify a highly orally bioavailable molecule. The acceptable solubility of 344 despite multiple aromatic rings is believed to be due to the out-of-plane bias of the methylpyrazole motif relative to the naphthyridine ring.

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 molecule is currently in clinical trials with hospitalized patients after demonstrating activity in healthy volunteers.

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 completed a Ph. I study in 2017, but there don’t appear to be any recent updates.

“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 pyrimidone nitrogen and a pyrazole nitrogen. The compound is bioavailable in rats (77% F) though the molecule potentially bears two negative charges at physiological pH (pyrimidone anion and carboxylate).

“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 substrate. The molecule possesses a rare alkyl -OCF3 functional group, which appears to have improved potency vs. other small lipophilic groups.

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 optimize compounds from immunosuppresive compounds with poor oral exposure to the non-immunosuppressive clinical candidate 5286 with oral activity in a mouse humanized liver HCV model.

(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 the molecule. This interesting mechanism is something to consider when observing unexpected cellular activities with solvent-exposed motifs in discovery programs!

Links to Articles:

  1. MK-5204
  2. “Compound 6f”
  3. GS-9688 (selgantolimod)
  4. JTE-052 (delgocitinib)
  5. “Compound 10”
  6. BAY 1895344
  7. JNJ-53718678
  8. BAY 1003803
  9. “Compound 19” (iron-binder)
  10. “Compound 2”
  11. “Compound 19”
  12. BI-0115
  13. ASP5286
  14. (R)-CR8

Hope enjoyed reading about these as much as I did. Explore for more.