Many more modalities, mechanisms, screening strategies, and interesting chemical motifs appeared from the drug discovery community in July. This time we have a compound from a DNA-encoded library screen, some compounds derived from phenotypic screens, and a starting point identified from a high-throughput mass screen. We also have the first cryo-EM structure featured this year from the GNF team at Novartis, and a co-crystal structure with a normally membrane-bound protein thanks to Sosei Heptares. Links to the articles and more discussion on specific molecules below.

Small Molecules of the Month - July 2020

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A-1331852 is a highly potent, orally bioavailable inhibitor of BCL-XL, blocking a protein-protein interaction resulting in tumor cell apoptosis. The compound was an important tool compound for understanding the biology of BCL-family protein inhibitors (particularly around heme toxicities), and ultimately led to the development of an antibody-drug conjugate (ABBV-155) which recently entered Ph. I studies for solid tumors. Andrew Judd gave a great presentation on the BCL-XL story at last year’s Bay Area Chemistry Symposium highlighting this project, and I’m looking forward to seeing the ADC part of the story being published in the future.

dotinurad (FYU-981) potently inhibits uric acid uptake by renal proximal tubule epithelial cells, increasing uric acid urinary secretion which can help hyperuricemic conditions like gout. The mechanism of action is believed to be inhibition of the URAT1 organic anion transporter which mediates uric acid reabsorption. Benzbromarone has been used for a long time in many countries to increase uric acid secretion, but is associated with rare but severe hepatic toxicities that are suspected to involve mitochondrial inhibitory activity. The authors therefore made mitigation of DILI risk a priority for this program and were successful in identifying a potent compound with low mitochondrial inhibitory activity.

X-165 is an autotaxin inhibitor clinical candidate for idiopathic pulmonary fibrosis discovered using a 3-cycle DEL screen of 225M compounds derived from amide couplings. An unusual spirocyclic amine building block was responsible for most of their non-phosphonate-containing high-enrichment hits. The initially resynthesized hits had single-digit nanomolar potencies in an enzymatic assay, and optimization for ADME properties while maintaining potency led to X-165.

“compound 38a” is an inhibitor of ChemR23, a chemokine-receptor-like GPCR with a role in plasmacytoid dendritic cell (pDC) trafficking. The ChemR23 inhibitor was developed with the intention of suppressing the migration of pDCs, which may be useful in certain autoimmune diseases. A key change that dramatically improved bioavailability was swapping a tetrazole with the 1,2,4-oxadiazol-5-one ring. The 1,2,4-oxadiazol-5-one is often proposed as a carboxylic acid isostere but I was surprised to see such a dramatic effect on bioavailability. It’s also surprising that the final compound, which bears two negatively charged groups (acid + oxadizolone) has significant oral exposure in monkeys.

HTL22562 is a CGRP antagonist intended to treat acute migraines. Some prior oral CGRP antagonists failed in clinical trials due to liver tox. signals, so this program targeted a non-oral candidate with lower first-pass liver exposure that might avoid such issues. Impressively the authors were able to drive the program through structure-based design thanks to X-ray co-crystal structures with the CGRP ectodomain complex. Structure-guided programs have been rare for membrane-bound proteins like GPCRs due to the challenge in crystallizing relevant forms of these targets.

“compound 23” is an oral, selective Factor XIa inhibitor intended as an anticoagulation agent. Since the clinical translatability of FXIa inhibition in preclinical models hasn’t been established, this program was driven by activity in in vitro human plasma coagulation assays. The team was able to turn a 0.6 uM hit originally from a complement factor D program into a subnanomolar FXIa inhibitor with excellent selectivity. I was surprised to see that the carboxylate plays an important role in binding to the target and is essentially desolvated in the co-crystal structure, given its normally high desolvation penalty. It was also impressive to see high oral exposure for a zwitterion containing a primary amine as well as often rapidly-metabolized benzofuran and indole groups.

MGS0274 is a prodrug of an mGlu2/3 receptor agonist with ca. 15x greater oral exposure than the parent. The ester is believed to be cleaved pre-systemically by liver carboxyesterases to release the innocuous byproducts acetaldehyde, CO2, and menthol. The parent is also an interesting looking molecule prepared in a few steps from cyclopentenone (ref. 9 in article).

LXE408 is an oral antileishmanarial compound that selectively targets the kinetoplastid proteosome vs. the mammalian proteosome. The prior candidate, GNF6702, had solubility-limited oral absorption, which could have been addressed with a specialized formulation but would have increased the cost and limited use in developing countries. A single methyl group dramatically improved the dissolution properties without compromising activity, leading to LXE408. Interestingly, a 3.4A cryo-EM structure was obtained of LXE408 with the kinetoplastid proteosome showing its non-competitive mode of binding in contrast to mammalian proteosome inhibitors like bortezomib.

“compound 2” is a heme-displacing IDO1 inhibitor with a similar binding mode to BMS-986205 with a low projected human dose. A bis-amide hit was generated from a mass-spectrometry based binding screen, and optimized through structure-based drug design. An initial benzamide lead was metabolically unstable due to rapid amide hydrolysis, but this was addressed by replacing a central phenyl ring with the bicyclo[1.1.1]propane (BCP) motif. While the BCP has been touted as a phenyl isostere, it is rare to see central phenyl groups replaced without significant losses in activity. Impressively, the BCP replacement led to a substantially improved series of molecules for the Merck team, convincing me to try this move more often!

AB680 is a potent (5 pM) and selective inhibitor of CD73, a nucleotidase that metabolizes AMP to immunosuppressive extracellular adenosine. AB680 is intended to be used in combination with checkpoint inhibitor biologics in cancer immunotherapy, and has a PK profile for biweekly (Q2W) IV dosing in humans based on a Ph. I study in healthy volunteers.

“compound 18” is an oral inducer of fetal hemoglobin (HbF) intended to treat anemias such as sickle cell disease and beta-thalassemia. The authors identified a weak hit (>10 uM) from a high-throughput phenotypic screen using human umbilical cord blood-derived erythroid progenitor cells. Optimization led to the azaspiro[3.3]heptane-containing compound 18, which demonstrated significant HbF induction in cynos without significant safety issues. The mechanism of action is unclear and will hopefully disclosed in the future.

ETX0282 is an oral prodrug of a class A, C, and D serine β-lactamase inhibitor in clinical development for drug-resistant enterobacterial infections in combination with the beta-lactam drug cefpodoxime proxetil. Impressively ETX0282 had no observed adverse effect levels (NOAELs) of 500 mg/kg/day and 400 mg/kg/day in rat and dog, respectively, despite the reactive-looking nature of the strained bridged carbamate core and the monofluoroether. I was surprised by the chemical stability of the fluoroether moiety, which can be seen in the co-crystal structure.

“compound 6g” is an oral inhibitor of the sodium-glucose co-transporters (SGLTs) 1 and 2, intended for the treatment of hyperglycemia. SGLT2 selective inhibitors (gliflozins) are approved for treatment of type 2 diabetes, and an SGLT1/2 dual inhibitor is expected to result in greater glycemic control. Like other SGLT inhibitors, this molecule is based on a natural product scaffold, and the analogs don’t look super easy to make (I was surprised to see a BAST difluorination proceed in 74% yield on a highly substituted ketone prone to elimination).

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 toxicity by targeting tumor cells expressing the folate receptor. I think the small molecule drug conjugate concept is an interesting one, though previous clinically tested molecules like vintafolide haven’t shown much promise yet. There’s probably a strong use case for this modality somewhere to be discovered!

Links to Articles:

  1. A-1331852
  2. dotinurad (FYU-981)
  3. X-165
  4. “compound 38a”
  5. HTL22562
  6. “compound 23”
  7. MGS0274
  8. LXE408
  9. “compound 2”
  10. AB680
  11. “compound 18”
  12. ETX0282
  13. “compound 6g”
  14. EC2629

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