In 2020 the Drug Hunter site highlighted >150 “molecules of the month” whose structures or stories were typically published for the first time. They were selected from thousands of research articles, published by leading institutions around the world. It was incredibly hard to narrow down the selection to just one molecule from each month, and it’s agonizing to leave so many amazing stories off this list, but here are 12 molecules from 2020 that our community would likely all agree we learned a lot from. The molecules were selected based on a range of factors, from clinical and commercial timeliness (such as Mirati’s market-moving KRAS inhibitor from April) to mechanistic proof of concept (such as GSK’s RIPK2 degrader with prolonged PD) to interesting modalities (such as Novartis’s reversible-covalent aldehyde FGFR4 inhibitor) to overcoming a brutal drug discovery campaign against a difficult mechanism of action (such as Gilead’s HIV capsid inhibitor).

When you’re done reading, vote for your favorite molecule here to help us identify the Drug Hunter community’s top molecule of 2021. No voting for your own institution, on the honor system 🙂

2020 Small Molecules of the Year

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January’s molecule, a Novartis FXR partial agonist (LMB763 (nidufexor)), modulates the farnesoid X nuclear receptor (FXR), a hot target for NASH due to promising prior clinical activity with bile acid-derived FXR agonists such as OCA. OCA, however, showed significant rates of side effects including itching (likely due to GPBAR1 bile acid receptor agonism) and elevated LDL cholesterol levels, which is problematic for the more heart-disease-susceptible NASH patient population. To complement their clinical, non-bile acid FXR full agonist, tripofexor, which addressed GPBAR1 selectivity, the Novartis team wanted a chemically distinct partial agonist candidate in case the elevated LDL levels turned out to be an on-target effect of FXR modulation. A high quality partial agonist starting point was identified from two parallel full-deck (3M compound) screening campaigns.

February’s molecule, the Novartis factor B inhibitor LNP023, targets the serine protease factor B (FB), a key node in the complement system. The complement part of the innate immune system is a hot area for drug discovery due to its increasingly recognized role in a wide range of chronic human diseases, including age-related macular degeneration (AMD). The authors took a pathway approach to drugging a portion of the complement system called the “alternative complement pathway” (AP), evaluating three different targets including FB. While proteases are tough drug targets due to their typically polar and frequently conserved active sites, the Novartis team was able to develop an oral, reversible, blood-retinal-barrier penetrant clinical candidate from a weak (10 uM) fragment identified through biochemical screening. While LNP023 doesn’t appear to have entered development for the treatment of ocular diseases, it is currently in multiple Ph. II studies for nephropathies.

March’s molecule, the GSK RIPK2 degrader “PROTAC 6”, demonstrates activity in vivo long after compound clearance due to the fact that the biological re-synthesis of its target is slow relative to clearance. The idea that degraders could have such unique extended PD in such situations is frequently thrown around, but hadn’t been explicitly demonstrated in vivo until GSK’s article. Though the compound hasn’t entered development, the article is an excellent case study for the optimization and rigorous evaluation of heterobifunctional degraders, complete with inactive isomeric controls. The GSK team observed phenomena including cellular activity far greater than what would be expected from RIPK2 binding due to the catalytic mechanism of degraders, found that small changes could increase compound potency by orders of magnitude, and ended up with a molecules that have long half lives (16 h) with biological activity at extraordinarily low doses (0.15 mg/kg once every 3 days). I bet this article becomes the most cited of this group 10 years from now.

April’s molecule, the Mirati KRAS G12C inhibitor MRTX849, has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the significant disease burden of KRAS-mutant-driven tumors in large indications including lung cancer. That Mirati’s KRAS clinical data has led to a nearly $10B appreciation in its equity value prior to an approval says everything about expectations for KRAS inhibitors in cancer. The recent successes of covalent inhibitors in cancer for targets like BTK, FGFR, and KRAS G12C are driving a major resurgence in interest for covalent inhibitors in modern drug discovery.

May’s molecule, the Daiichi Sankyo NaV1.7 inhibitor DS-1971a, is a potent, isoform-selective agent that was intended to treat neuropathic pain. NaV1.7 has been a hot target for pain due to significant human genetic evidence for its role in pain, and non-opioid analgesics are badly needed. The compound has a surprisingly long residence time on NaV1.7, which the authors suggest contributes to better than predicted in vivo activity. It’s a good example of a compound which was successfully advanced to clinical trials despite a PK disconnect between rodents and higher species. 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 was one of the first clinically tested NaV1.7 inhibitors, entering clinical development several years ago. While it was found to be safe in healthy volunteers in a phase I study, it was discontinued in Ph. II, and served as a harbinger for the other discontinuations since.

June’s molecule, the BMS factor XIa inhibitor “Compound 6f”, is a potent, oral macrocyclic factor XIa inhibitor (<1 nM) that was intended as an anticoagulation agent. Since blood clotting is a significant risk for hospitalized patients that must be in a bed for days or weeks, anticoagulants are some of the most prescribed and impactful drugs in the pharmacopeia. “6f” is highly selective against other serine proteases and has excellent oral PK (high bioavailability, low clearance). Though “6f” did not progress due in part to solubility issues, the progress against a challenging target using a difficult macrocyclic scaffold is impressive.

July’s molecule, the AbbVie BCL-XL inhibitor A-1331852, is a highly potent, orally bioavailable, protein-protein interaction inhibitor which triggers tumor cell apoptosis. The molecule emerged from a long, challenging fragment-assisted discovery campaign, as might be expected for a formerly “undruggable” target. The compound was an important tool compound for understanding the on-target biology of BCL-family protein inhibitors (particularly with respect to heme toxicities), and ultimately led to the development of a safer antibody-drug conjugate (ABBV-155) which recently entered Ph. I studies for solid tumors. Impressively, it was the AbbVie chemistry team that pushed to successfully continue the BCL-XL program with a biologic modality.

August’s molecule, the Gilead HIV capsid inhibitor GS-6207, is an HIV-1 inhibitor that took over 12 years to develop due to its challenging mode of action. It acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is able to overcome the high concentration of p24 in a virion (~4 mM!) to inhibit HIV activity with sub-nanomolar potency in cells (20-500 pM). Since the HIV capsid protein is highly conserved among HIV-1 variants, GS-6207 shows high synergy and no cross-resistance with approved anti-HIV agents. GS-6207 was found to be generally safe and well-tolerated in Ph. I and showed evidence of antiviral activity. Amazingly, this small molecule has the half-life one might expect of a well-engineered biologic drug, and is being dosed subcutaneously once every 6 months in the Ph. II/III study.

September’s molecule, the Novartis FGFR4 inhibitor FGF401 (roblitinib), is a highly selective, reversible-covalent kinase inhibitor. The FGFR4 receptor has been a hot target recently due to its role in driving progression of certain cancers. The Novartis team found that the FGFR4 protein has a high re-synthesis rate and therefore would require significant drug exposure to have a meaningful effect, so they deprioritized irreversible covalent starting points and pursued a potentially safer reversible-covalent strategy instead. The aldehyde of roblitinib targets a unique Cys by the hinge region of the protein (GK+2) that is not present in the other FGFR’s and is present in only 4 other kinases. It is impressive that they were able to optimize an aldehyde for clinical oral dosing, and given the recent approval of another remarkable aldehyde drug, voxelotor, it’s aldehydes are sure to become a more widely tested drug motif in the future. This Novartis molecule is certain to be regarded as a “classic” in drug discovery for some time.

October’s molecule, the Bayer hGnRH-R antagonist BAY 1214784, is intended as an oral, once-daily treatment for uterine fibroids, a highly common problem in adult women that can lead to infertility. Existing treatments include hGnRH-R blockers which have undesirable side effects such as induction of menopausal symptoms due to their influence on both LH and FSH hormone levels. The chemically distinct Bayer molecule differentiates from prior molecules by having a PK/PD profile that allows only partial lowering of LH levels only. The bar for safety in a large indication with otherwise healthy individuals is very high, but BAY 1214784 successful advanced to clinical testing and completed a Ph. I study with good tolerability at doses up to 450 mg QD.

November’s molecule, the Chugai/Lilly GLP-1R agonist LY3502970, is a highly potent and selective, oral, biased partial agonist of the GLP-1R GPCR. GLP-1R agonists have been approved for many years now to treat Type II diabetes mellitus, due to their ability to stimulate insulin secretion in pancreatic beta-cells. However, until recently, all GLP-1R agonists were all non-orally available peptides, requiring subcutaneous injection. The development of oral GLP-1R agonists has thus been a hot area in metabolic disease research, but GLP-1R has turned out to be an exceptionally challenging GPCR to drug with the desired mode of action, as the structure of LY3502970 implies! The article describes this molecules interesting mechanism of action with significant structural detail thanks to Cryo-EM, and LY3502970 is currently in trials as an antidiabetic agent. Had Pfizer’s oral GLP-1R agonist not been published in September, it could have also easily been a “molecule of the year.”

Finally, December’s molecule, the Novo Nordisk oral insulin analog OI338, is the first oral insulin to demonstrate similar outcomes to insulin glargine injection in a Ph. II clinical trial. The molecule has an ultralong PK profile (t1/2 = 70 h) due to the inclusion of an albumin-binding long-chain fatty acid. Though the human doses of OI338 are high enough to challenge commercial access, the technical achievement of achieving oral activity in human with such a complex peptide is outstanding.

Links to Articles:

  1. JanuaryLMB763 (nidufexor) – Novartis FXR Agonist
  2. FebruaryLNP023 – Novartis Factor B Inhibitor
  3. March“PROTAC 6” – GSK RIPK2 Degrader
  4. AprilMRTX849 – Mirati KRAS Inhibitor
  5. MayDS-1971a – Daiichi Sankyo NaV1.7 Inhibitor
  6. June“Compound 6f” – BMS Factor XIa Inhibitor
  7. JulyA-1331852 – AbbVie BCL-XL Inhibitor
  8. AugustGS-6207 – Gilead HIV Capsid Inhibitor
  9. SeptemberFGF401 (roblitinib) – Novartis FGFR4 Inhibitor
  10. OctoberBAY 1214784 – Bayer hGnRH-R Antagonist
  11. NovemberLY3502970 – Chugai/Lilly GLP-1R Agonist
  12. DecemberOI338 – Novo Nordisk Oral Insulin Analog

I hope you enjoyed 2020’s highlights, and find 2021 just as helpful. Don’t forget to vote for your favorite molecule here! Explore for more.