April 2020 was another great month for drug discovery publications, with several interesting first disclosures of clinical candidates and a variety of uncommon chemical motifs that will pique most chemists’ interest. Here’s a visual summary of the molecules, with some comments and links to the articles below:

Small Molecules of the Month - Apr. 2020

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Tucatinib is the third approved HER2 kinase inhibitor (after lapatinib and neratinib), but differentiates itself due to its selectivity against the closely related EGFR, which is hypothesized to be a source of undesired side effects with prior inhibitors. Impressively, it’s also demonstrated activity in HER2+ breast cancers with brain metastases. Chemically, it’s got an interesting, uncommon oxazoline unit, and three pretty electron-rich aromatic rings which don’t seem to have prevented tucatinib’s administration as an oral BID drug. However the drug label does note hepatotoxicity as an uncommon adverse event contributing to ~8% of patients needing dose reductions and 1.5% discontinuing the drug.

S6821 is one of two potent and selective TAS2R8 GPCR antagonists disclosed by Firmenich, a fragrance and flavor company. These compounds block bitter taste receptors and don’t have significant systemic exposure, and have been approved as safe for use. I thought it was interesting to see high-quality medicinal chemistry applied in a non-traditional setting.

MRTX849 is one of the hotly followed KRAS G12C inhibitors in clinical development, and it’s discovery campaign was first disclosed in April. It’s the second of two drugs on this list that the prolific Array Biopharma (now Pfizer Colorado) had a hand in. It certainly doesn’t look like an easy scaffold to have optimized for oral delivery!

BAY1161909 is one of two clinical candidates disclosed in a single paper from Bayer. The compounds have an interesting anti-cancer mechanism – rather than inhibiting cancer cell growth, they accelerate cancer cell cycle progression, leading to cell death due to a high degree of chromosomal misaggregation. 909 was discovered through an HTS and optimization campaign, while the second candidate was developed from a known starting point. Development on 909 appears to have been paused in favor of the second candidate.

ORN0829 is a dual inhibitor of orexins 1 and 2, designed to have a relatively short half life in humans for application in insomnia (to reduce side effects after waking up). Chemically it has an interesting chiral 1,3-oxazinane amide motif, which is resolved in their med. chem. route through an enzymatic resolution.

BMS-986251 is an inverse agonist of RORgt, a hot target in inflammation for a significant period. Unfortunately it looks like development hit a wall in this space, and several publications of various company’s RORgt modulators have appeared in the last several months. Chemically, 251 is interesting with 5 stereocenters, none of which look particularly easy to set. Looking forward to the process paper on this one!

GSK2818713 is an HCV NS5A replication complex inhibitor with an interesting biphenylene linker. The crowded, hotly competitive NS5A space has led to a lot of creative chemical scaffolds including this one.

CPI-1612 is a pretty efficient-looking EP300/CBP histone acetyltransferase (HAT) inhibitor tool compound with demonstrated activity in a xenograft model and good higher species PK. While epigenetics targets like HATs have been hot this decade, many programs have run into tolerability challenges and/or difficulty identifying activity biomarkers. It doesn’t look like CPI-1612 entered development so it’s likely the program encountered similar issues. While irrelevant for a tool compound, it’s interesting that they were able to abrogate in vitro hERG activity in an early indole series by switching to the 2-amidopyridine scaffold in CPI-1612.

“Compound 19” is a JAK1/TYK2 dual kinase inhibitor from Pfizer, related to its clinical JAK1/TYK2 dual inhibitor, brepocitinib, in Ph. II for a variety of inflammatory diseases. The cyclopropyl amide group was designed to displace a high energy water molecule. It was probably fortunate for their manufacturing colleagues that brepocitinib was taken forward instead, as the [3.1.0] core of this molecule was prepared through a Ti-mediated cyclopropanation in <20% yield.

AZD4205 is a JAK1-selective kinase inhibitor which is in clinical development for oncology rather than the inflammatory diseases most JAK1 inhibitors have aimed for. The compound has excellent PK in dog, and the authors demonstrate that JAK1 inhibition doesn’t have strong single-agent activity in a xenograft model but can synergize significantly with an EGFR-kinase inhibitor. The azaindole amide makes an uncommon bidentate interaction with the DFG-loop aspartate residue.

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with activity against both serine and zinc metallo-beta-lactamases, in contrast to approved beta-lactamase inhibitors such as relebactam which are only active against serine metalloproteases. Interestingly, the boron of the molecule coordinates to serine hydroxyl groups in serine beta-lactamases, whereas it coordinates as a boronate ligand to the zinc centers of metallo-beta-lactamases.

“Compound 9” is the first potent M3-selective positive allosteric modulator, with potential utility as a biological tool compound. It does have secondary activity against M5 at high doses though. It’s quite a large zwitterion, which is somewhat unusual for GPCRs.

“Compound (P)-14″ is a PI3K beta-isoform selective lipid kinase inhibitor. While the compound is potent and has excellent oral PK in higher species, significant irreversible toxicity was observed in a tox. study, and the chemical series was discontinued. It’s always great when organizations disclose tox. findings to educate the community. Interestingly the molecule has a significant barrier to rotation around the benzimidazole ring and can be isolated as a stable atropisomer.

FT385 is a covalent inhibitor of the USP30 deubiquitinating enzyme with a cyanopyrrolidine warhead. Identifying selective active-site inhibitors of de-ubiquitinating enzymes has been challenging, and FT385 now provides a good tool compound to study USP30 biology. Some of my colleagues at Genentech recently published on the mechanism of cyanopyrrolidine inhibition of USP7, which proceeds through an interesting de-sulfhydration reaction.

Links to Articles:

  1. tucatinib
  2. S6821
  3. MRTX849
  4. BAY1161909
  5. ORN0829
  6. BMS-986251
  7. GSK2818713
  8. CPI-1612
  9. “Compound 19”
  10. AZD4205
  11. QPX7728
  12. “Compound 9”
  13. “Compound (P)-14″
  14. FT385

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