Here’s May’s round-up of small molecule highlights, with comments and links to articles below. There was a lot of diversity among targets last month, although there were surprisingly few structure-based campaigns disclosed. Plenty of interesting biology and chemical structures to consider!

Small Molecules of the Month - May 2020

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eFT226 (zotatifin) is a beautiful natural product-derived molecule that inhibits the RNA helicase eIF4A by forming a ternary complex between it, eIF4A, and polypurine RNA. Interestingly, the stability of the ternary complex depends on the RNA sequence bound to eIF4A, with greatest activity for AGAGAG-based complexes. The molecule demonstrates significant activity in tumor xenografts with once weekly dosing of as little as 1 mg/kg compound IV and entered clinical development last year. Chemists will appreciate the neat photocycloaddition/ketol-rearrangement used to synthesize the compound. I’m looking forward to learning how this was scaled up for clinical development!

DS-1971a is a potent, isoform-selective selective arylsulfonamide NaV1.7 inhibitor intended for the treatment of neuropathic pain. It has a surprisingly long residence time on NaV1.7, which the authors suggest contributes to better than predicted in vivo activity. 1971a is a good example of a compound which was successfully advanced to clinical trials despite a PK disconnect between rodents and higher species (much lower clearance in higher species than in both mice and rats). There’s also an enormously high bar for safety in pain indications, and in preclinical safety studies, this compound was very well-tolerated in both rodents and cynos (NOAEL = 1000 mg/kg!). It entered clinical development several years ago, and was found to be safe in healthy volunteers in a phase I study, but was discontinued in Ph. II.

BMS-986235/LAR-1219 is an FPR1-sparing FPR2-selective agonist intended to help resolve chronic inflammation/promote wound healing to prevent serious complications like heart failure. It’s a very efficient molecule and is orally efficacious in a mouse myocardial infarction model at doses as low as 0.3 mg/pk, despite having 3 N-H donors (urea + amide) in its core. Like DS-1971a it has a PK disconnect between species (significantly lower clearance in higher species than in rodents) but was successfully taken into development. Human data hasn’t been reported yet.

JNJ-54717793 is a selective antagonist of the orexin-1 receptor intended for use in anxiety disorders, in contrast to dual orexin-1/2 inhibitors and orexin-2 inhibitors typically applied for sleep disorders. It’s a surprisingly large molecule (three aromatic rings and a bicycle) for an oral, brain-penetrant clinical candidate with predicted once-daily dosing in humans. This compound was very well-tolerated in preclinical species (NOAEL 250 mg/kg in rodent, 25 mg/kg in dog).

“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 microsomal stability over the corresponding piperidine analog without a significant change in cLogD. The compound demonstrated activity in a xenograft model at doses as low as 0.5 mg/kg QD.

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 desirable to avoid the associated risk of further developing endometrial cancer in breast cancer patients.

[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 substitution onto a nitropyridine.

RO7185876 is a gamma-secretase modulator (GSM) intended for treatment of Alzheimer’s disease. GSMs, which act by stabilizing the enzyme/substrate complex to promote generation of shorter peptides rather than inhibiting enzyme activity, and hence are anticipated to be less toxic than gamma-secretase inhibitors (GSI’s) which were abandoned due to serious safety liabilities. This compound competed two-week toxicology studies in two species (including one non-rodent), supporting its potential advancement to GLP tox. studies.

ONO-8430506 is a potent autotaxin phosphodiesterase inhibitor with significant oral exposure and low clearance in higher species. Autotaxin contributes to lysophosphatidic acid (LPA) production has been explored as a target in various diseases involving LPA signalling including IPF (GLPG1690, Ph. III), hyperplasia, and cancer (this paper). ONO-8430506 was first disclosed several years ago but the details around its discovery are disclosed here, including the clever strategy to “hybridize” an HTS hit with an endogenous ligand.

“Compound 15” is a BACE1 selective inhibitor with a fluoro-olefin replacement for an N-aryl amide without the liability of a potential aniline metabolite. The compound has good oral PK in rodents, which was likely challenging to obtain with the thioamidine core common to BACE1 inhibitors. As usual for Amgen there’s some pretty cool synthetic chemistry in the cited patents for this thiazine scaffold (ref. 17) that’s worth taking a look through.

NLG802 is a prodrug of the IDO1 inhibitor indoximod with significantly enhanced oral exposure. Both the acid and amine functionalities of indoximod are protected as an ethyl ester and leucine amide, respectively. Prodrugs are generally difficult to develop so it’s interesting that two biotransformations are employed. The molecule is first cleaved to the carboxylic acid by carboxyesterases CES1b and CES1c, which is then further cleaved by unidentified peptidases to release indoximod.

“Compound 6g” is a potent, selective, and reversible inhibitor of monoacylglycerol lipase (MAGL), which degrades the cannabinoid receptor (CB) agonist 2-arachidononylglycerol (2-AG) to arachadonic acid (AA). Inhibition of MAGL therefore indirectly agonizes CB receptors and reduces inflammatory AA levels, which may be beneficial for a range of disorders. In contrast to most prior MAGL inhibitors which are covalent modifiers, this compound is a reversible inhibitor.

GSK232 is a highly selective cell-penetrant inhibitor of the non-BET CECR2 bromodomain with >500-fold selectivity over BET-family bromodomains identified during a campaign to find selective inhibitors of the bromodomain ATAD2. Since bromodomain-containing complexes are highly modular and have scaffolding functions, their roles in biology are difficult to study without tool molecules. Hence new selective tool molecules for bromodomain family members are invaluable for basic biology research. Co-crystal structures of related compounds on ATAD2 suggest the involvement of a halogen bond with a protein carbonyl, as well as a hydrogen bond involving a sulfonamide oxygen despite the sulfonamide’s relatively weak H-bond accepting ability.

LEI401 is a selective, brain-penetrant inhibitor of NAPE-PLD, an enzyme involved in the biosynthesis of various N-acylethanolamine (NAE) signaling lipids, and is a potentially useful tool molecule for understanding the basic biology around this target. The compound emerged as the result of an academic collaboration, including an HTS done with the European Lead Factory. This looks to be a promising example of how academic institutions can collaboratively generate and validate useful tools for basic research.

Finally, if you’re still looking for more reading after all that, my former colleagues at RAPT Therapeutics recently published an article on our work on allosteric inhibitors of the deubiquitinating enzyme, USP7. It was an interesting and challenging target to address though the compounds haven’t entered clinical development.

Links to Articles:

  1. eFT226 (zotatifin)
  2. JNJ-54717793
  3. DS-1971a
  4. BMS-986235/LAR-1219
  5. “Compound 34”
  6. GNE-149
  7. [18F]LSN3316612
  8. RO7185876
  9. ONO-8430506
  10. “Compound 15”
  11. NLG802
  12. “Compound 6g”
  13. GSK232
  14. LEI401

Hope this is helpful and stay safe. Explore for more.