For the first installment of Drug Hunter’s “Small Molecules of the Month” series in 2021, we have a Kissei SGLT2 inhibitor whose lead was a metabolite found in mouse urine, a GSK integrin inhibitor that was found to trigger lysosomal degradation, and the first non-sugar OGA inhibitor derived from a Takeda virtual screen. Plenty of interesting reading here to start your year – more details, links, and the PDF download below.

PF-06843195 prodrug
“compound 42”
“compound 12”
“compound 1”

Small Molecules of the Month - Jan. 2021

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  1. The Kissei SGLT2 inhibitor prodrug, remogliflozin etabonate, is an SGLT1-sparing oral drug launched in 2019 in India for the treatment of type 2 diabetes.  Interestingly, the lead for this drug was a metabolite identified from mouse urine after treatment with a Wyeth-Ayerst antihyperglycemic agent of previously unknown mechanism. 
  2. The Galapagos CFTR potentiator, GLPG2451, is an oral, once-daily clinical candidate for cystic fibrosis (5-80 mg QD).  It was advanced into a high-profile Ph. II triple-combo study with the CFTR correctors GLPG2737 and GLPG2222 in partnership with AbbVie, and was seen as a potential competitor to Vertex’s CF franchise, but unfortunately weak efficacy data appears to have ended development.  The GLPG team was able to get away from their original thiophene core by conducting an interesting scaffold hop in which a hydrogen bond donor and acceptor were swapped across a ring, resulting in their much nicer looking final scaffold.
  3. The Boehringer RORγ antagonist, BI 730357, is an oral once-daily clinical candidate from a new compound class in development for plaque psoriasis.  We highlighted two other RORγ modulators last year in February and March.  While most clinical RORγ modulators have discontinued development after reaching Ph. II, BI 730357’s Ph. II trial appears to be on-going. 
  4. The Merck LRRK2 inhibitor, MLi-2, is an orally available tool compound that is structurally distinct from the LRRK2 inhibitor GNE-7915.  LRRK2 had been a highly attractive target for treating Parkinson’s disease, but pulmonary toxicity observed with LRRK2 inhibition in non-human primates (NHP) cast a shadow on the utility of LRRK2 inhibitors.  Since NHP studies are cost and resource-intensive, it was difficult to study the toxicity in depth. The Merck team was able to recapitulate the pulmonary toxicity in rodents with MLi-2, and found that the lung effects were due to chronic LRRK2 inhibition and were mild and readily reversible.  This study provides a higher-throughput method to assess new LRRK2 inhibitor scaffolds and more broadly understand on-target effects of LRRK2 inhibition.
  5. The GSK αvβ6 integrin inhibitor, “compound 1,” or GSK 3008348 is a previously reported IPF clinical candidate that is a picomolar binder to αvβ6 with slow dissociation kinetics.  The recent report highlights the fact that the compound results in prolonged effects in cells by triggering integrin internalization and lysosomal degradation.  While this phenomena of small molecule-induced receptor internalization/degradation has been characterized in other transmembrane receptors such as GPCRs, it hasn’t been well-studied in integrins. Small molecule integrin modulators are seeing renewed interest for indications such as fibrosis, and this induced lysosomal degradation pharmacology is worth keeping in the mental toolbox for targeting integrins and other transmembrane proteins.
  6.  The Takeda O-GlcNAcase (OGA) inhibitor, “compound 5i,” binds to the same site as prior sugar-based OGA inhibitors, but has surprisingly different chemical properties and a unique binding mode.  The Takeda team realized that polar, sugar-based OGA inhibitors would be challenging to get into the brain where they would be needed for neurodegenerative diseases, and so used an elegant virtual-screening and structure-based approach to make the leap to the distinct, CNS-friendly starting point for compound 5i.  The less basic pyrimidine N(1) nitrogen (pKa ~ 4.9) surprisingly appears to be protonated in the binding site, making a bidentate interaction with a carboxylate, likely helped by the presence of a second Asp residue.  The article is a great case-study for identifying distinct new chemical matter through a rational approach, and the new brain-penetrant OGA inhibitor should be a useful in vivo tool compound for understanding the treatment of neurodegenerative disorders.
  7. The Eisai β-catenin/CBP inhibitor, E7386, is an orally active and selective inhibitor of the β-catenin/CBP protein-protein interaction, a key node in the long studied Wnt/β-catenin pathway in cancer.  Prior attempts to drug Wnt directly were met with severe toxicity in clinical trials.  The pathway has seen a resurgence in interest due to its potential role in tumor immune evasion, and the Eisei team demonstrates that E7386 synergizes with anti-PD-1 in a syngeneic model.  E7386 is currently in a Ph. I study as a monotherapy for solid tumors.
  8. The Novartis BET bromodomain inhibitor, NVS-BET-1, is a new chemotype of BRD4 (BD1 and BD2) inhibitor.  While we recently highlighted a few high-profile, selective bromodomain inhibitors from AbbVie and GSK, the Novartis team took a different approach to reaching their molecules.  The Novartis team was looking for mechanisms that influence keratinocyte differentiation to treat wound healing, and identified BET inhibitors in a phenotypic screen.  Interestingly, their proprietary matter emerged from a BRD4 biochemical screen that identified a totally unrelated p53-MDM2 inhibitor as a moderately potent hit.  Optimization led to NVS-BET-1 which potently influences wound healing when administered orally at doses as low as 1 mg/kg.  The wound-healing effects however, were lost at higher concentrations, recapitulating the “bell-shaped” dose-response curves from in vitro assays.
  9. The BMS HIV-1 maturation inhibitor, “compound 16,” is a potent derivative of the clinical candidate GSK3532795/955176, with double-digit nanomolar activity in cells.  The spiro[3.3]hept-5-ene effectively replaces a phenyl ring its parent molecule.  Though it wasn’t taken beyond an in vitro assay, the structure is worth noting in the mental isostere toolbox.
  10. The JNJ AR antagonist, JNJ-63576253, is a clinical molecule for prostate cancer that is active against both wild-type androgen receptor as well as the clinically relevant AR mutant, F877L.  F887L is a devious resistance mechanism that transforms antagonists of AR into agonists.  The parent compound from which 6253 is derived was found to be unacceptably hepatotoxic, which was suspected to be due to bioactivation of an electron rich phenyl ring.  Replacing the phenyl ring with a pyridine, an often-effective strategy for mitigating bioactivation of aryl amines, led to the dramatically improved safety window observed for JNJ-63576253. JNJ-63576253/TRC-253 recently completed a Ph. I/II trial in mCRPC.
  11. The Henan EGFR inhibitor, dosimertinib, is a deuterated derivative of the approved covalent inhibitor, osimertinib.  A metabolite of osimertinib, AZ5104, has lower selectivity for WT EGFR than mutant EGFR, which the authors suggest may contribute to some adverse events.  Deuteration of osimertinib appears to reduce the formation of the AZ5104-like metabolite in vitro and in vivo.  Dosimertinib appears to have a wider therapeutic window in mice than osimertinib based on doses at which mouse body weight loss is observed, and is currently starting a Ph. I trial in China to evaluate this hypothesis in humans.
  12. The BMS IDO1 inhibitor, BMS-986242, is a clinical candidate in a Ph. I/II study in combination with nivolumab for cancer.  Like me, you probably had to look twice at this molecule since it’s so similar to linrodostat, which we covered recently.  Forming the reverse amide of linrodostat appears to improve the PK profile and also removes a potential reactive aniline metabolite.  Making the reverse amide of an amide starting point is a med. chem. tactic that’s often suggested, but it’s rare to see it play out so well, especially when both the amide H-bond donor and acceptor making interactions with the target.
  13. The CellCentric p300/CBP inhibitor, CCS1477, is an orally available drug in early development for advanced prostate cancer, and is structurally distinct from the p300/CBP inhibitor we covered in Apr. 2020.  In agreement with its proposed MoA, it impacts AR and MYC signaling in serial tumor biopsies acquired from its first-in-human Ph. I trial.  It will be interesting to  see whether the agent is able to demonstrate a significant survival and quality-of-life benefit in late-stage disease given the likely on-target effects of p300/CBP inhibition on certain healthy cells.
  14. The academic covalent ALKi inhibitor, Con B-1, is thought-provoking initial proof-of-concept that remote kinase cysteines might be targetable from an active-site inhibitor. The authors show that a derivative of ceritinib with a remote electrophile attached can inhibit ceritinib more potently than a non-reactive control compound, that linker length significantly impacts activity, and that a 1:1 compound:ALK adduct can be detected on incubuation with an excess of reactive compound.  The proposed MoA would be more convincing with an X-ray co-crystal structure rather than a docking model, or with a comparison to an appropriate Cys->Ala mutant, but it is worth considering this strategy in other contexts.

Links to Articles:

  1. Remogliflozin etabonate
  2. GLPG2451
  3. BI 730357
  4. MLi-2
  5. compound 1
  6. compound 5i
  7. E7386
  8. NVS-BET-1
  9. compound 16
  10. JNJ-63576253
  11. Dosimertinib
  12. BMS-986242
  13. CCS1477
  14. Con B-1

Hope this is helpful. P.S. We’ve finally dropped the hyphen! Update your bookmarks and explore for more.