Medicinal chemists revealed the structures of a dozen clinical candidates during the “First-Time Disclosures” symposium on March 26 at the American Chemical Society Spring 2025 meeting in San Diego. Schrödinger’s H. Rachel Lagiakos, who organized the perennially popular session on behalf of the ACS Division of Medicinal Chemistry, promised attendees that it would be “an incredible day of science.” Hundreds of attendees packed into a conference room to see the new molecules, which could become drugs for fighting infections, cancer, neurological disorders, and cardiovascular disease.
Candidate: FG-2101
Presenter: Seth Cohen, University of California, San Diego (UCSD) and Blacksmith Medicines
Target: Uridine diphosphate-3-O-(hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC)
Disease: Gram-negative bacterial infections
UCSD chemistry professor Seth Cohen cofounded Blacksmith Medicines hoping to find molecules that can target metalloenzymes. Roughly one-third of enzymes have metals in their active sites, Cohen said, so this is a rich area for drug discovery. One such enzyme is LpxC, a zinc hydrolase that is found in gram-negative bacteria but not gram-positive bacteria or human cells. Drugs specific for gram-negative bacteria could fight urinary tract infections, for example, without killing off good bacteria in the gut.
Other molecules designed to bind to LpxC use hydroxamic acids to coordinate to the enzyme’s zinc ion. These have not fared well in clinical trials, and no drugs currently on the market target LpxC. FG-2101 contains a different metal-binding motif: 3-hydroxy-2-pyrimidinone, which was discovered using a fragment-based drug discovery approach. The compound is poised to enter clinical trials later this year. “I’m really proud as an academic to achieve something that will hopefully change lives,” Cohen said.
Candidate: PRT3789
Presenter: Corey Basch, Prelude Therapeutics
Target: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2)
Disease: Solid tumors
Targeted protein degradation has become a popular approach in cancer drug development. Prelude Therapeutics’ Corey Basch spoke about PRT3789, a degrader aimed at SMARCA2. This protein drives cell growth in cancers that are deficient in or have mutations in the protein SMARCA4. For example, roughly 10% of people with non-small-cell lung cancer have SMARCA4-deficient tumors.
The challenge in developing PRT3789 was finding a compound that degrades SMARCA2 and not SMARCA4, which is also present in some noncancerous cells and shares a similar bromodomain, an area of proteins that mediates interactions with other proteins. In the middle of PRT3789 is a chiral methyl group that Basch and colleagues think is key to guiding the degrader’s conformation so that it selectively makes a complex with SMARCA2 and von Hippel-Lindau E3 ligase, which sends SMARCA2 off to the body’s protein disposal pathway. PRT3789 is currently in Phase 2 clinical trials (NCT06682806) in combination with Keytruda (pembrolizumab) in people who have advanced, recurrent, or metastatic solid tumors with a SMARCA4 mutation.
Candidate: BMS-986458
Presenter: Deborah Mortensen, Bristol Myers Squibb
Target: B-cell lymphoma 6 protein (BCL6)
Disease: B-cell non-Hodgkin’s lymphoma
Deborah Mortensen unveiled the session’s second targeted protein degrader, Bristol Myers Squibb’s BMS-986458. This compound targets BCL6, a protein that is involved in normal B-cell development but whose level is often elevated in B-cell cancers. Mortensen said BCL6 was once thought to be undruggable. BMS-986458 links BCL6 with cereblon, another protein that sends proteins off for disposal.
BMS-986458 features three stereocenters, one of which epimerizes easily, Mortensen said. The drug candidate, which would be taken orally, is currently in Phase 1 clinical trials (NCT06090539) alone and in combination with antilymphoma drugs in people who have relapsed or refractory non-Hodgkin's lymphoma.
Candidate: RP-1664
Presenter: Frédéric Vallée, Repare Therapeutics
Target: Serine/threonine-protein kinase/polo-like kinase 4 (PLK4)
Disease: Solid tumors, pediatric neuroblastoma
Centrinone B was the starting point for Repare Therapeutics’ drug candidate RP-1664, according to Repare’s Frédéric Vallée. In cells, centrinone B is an excellent inhibitor of PLK4—a kinase that’s found in certain types of tumors. The problem is that centrinone B gets metabolized quickly and is not bioavailable. So scientists at Repare started by working on absorption, distribution, metabolism, and excretion (ADME) of their compounds. “We fixed our ADME properties first and then went for potency. That was pivotal,” Vallée said.
Although there are many structural differences between RP-1664 and centrinone B, Vallée pointed out that a cyclopropyl group in RP-1664, which replaces a methoxy group in centrinone B, is key to the molecule’s potency and selectivity. RP-1664 is in Phase 1 clinical trials (NCT06232408) for treatment of advanced solid tumors. If approved, it would be a first-in-class drug.
Candidate: BMS-986238
Presenter: Paul M. Scola, Bristol Myers Squibb
Target: Programmed death-ligand 1 (PD-L1)
Disease: Solid tumors
Bristol Myers Squibb’s Paul M. Scola presented what was, without question, the session’s largest clinical candidate. BMS-986238 is a second-generation version of the company’s macrocyclic peptide BMS-986189, which inhibits the cancer target PD-L1 but has a short half-life in the body. To improve the macrocyclic peptide’s pharmacokinetics, scientists at the company decided to add a fatty acid to the molecule so it would bind to serum albumin and enhance its lifetime. Weight-loss medicines like Wegovy and Zepbound use a similar strategy to achieve weekly dosing.
The researchers found that they had to put space between fatty acid and peptide macrocycle, so a polyethylene glycol chain separates these moieties in the molecule. Scola said that it was a good general strategy for making peptide macrocycles into drug candidates. BMS-986238 could be given weekly by subcutaneous injection. Oral dosing, which was achieved via formulation, would be daily. BMS-986238 recently completed a Phase 1 clinical trial (NCT06568458).
Candidate: ALKS 2680
Presenter: Brian Raymer, Alkermes
Target: Orexin receptor type 2 (OX2R)
Disease: Narcolepsy and idiopathic hypersomnia
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness that often goes undiagnosed. Alkermes’s clinical candidate ALKS 2680 targets OX2R, which plays an important role in the body’s sleep-wake cycle.
Other molecules that bind OX2R have a C shape, so the company’s chemists decided to create macrocycles that used a covalent linker to lock this C-shaped conformation into place. Alkermes’s Brian Raymer said that when the scientists were building ALKS 2680, “a very careful design of the linker was paramount.” ALKS 2680 is currently in several clinical trials, including a Phase 2 trial for narcolepsy type 1 (NCT06358950).
Candidate: IAMA-6
Presenter: Marco Borgogno, Iama Therapeutics
Target: Sodium-potassium-chloride cotransporter 1(NKCC1)
Disease: Neurological disorders, including autism spectrum disorders, Down syndrome, and drug-resistant epilepsy
Iama Therapeutics’ Marco Borgogno began designing the molecules that would lead to the company’s clinical candidate IAMA-6 as part of his doctoral work at the University of Bologna. His goal was to find molecules that would target chloride transporter NKCC1, which is associated with chloride imbalance in the brain—a hallmark of certain neurological conditions, including autism spectrum disorders, Down syndrome, and drug-resistant epilepsy.
The challenge, Borgogno said, was to make a molecule that wouldn’t also hit NKCC2, a related protein that has diuretic effects. IAMA-6 accomplishes this task and also penetrates the blood-brain barrier. It recently completed Phase 1 clinical trials (NCT06300398). Borgogno said Iama hopes to begin Phase 2 trials in 2026.
Candidate: ORIC-114
Presenter: Anthony Romero, Oric Pharmaceuticals
Target: Exon 20 insertions of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)
Disease: Non-small-cell lung cancer with EGFR/HER2 mutations
People who have non-small-cell lung cancer with exon 20 insertions in EGFR or HER2 often develop metastases in their brains over the course of their disease. Unfortunately, the drugs available to treat these cancers don’t cross the blood-brain barrier. Anthony Romero of Oric Pharmaceuticals spoke about ORIC-114, a molecule that targets these exon 20 insertions by making a covalent bond to them.
“When you first look at the molecule, you would not think this this is brain penetrant,” Romero said. But the company has already seen early success in its Phase 1b clinical trials (NCT05315700). Romero told the story of one 55-year-old woman in the trial who had four brain lesions that disappeared after one round of treatment with ORIC-114, and her lung cancer responded after two rounds of treatment. What’s more, Romero said, the woman had not been eligible for other clinical trials because her disease was so advanced.
Candidate: AZD2389
Presenter: Anneli Nordqvist, AstraZeneca
Target: Fibroblast activation protein (FAP)
Disease: Metabolic dysfunction–associated steatohepatitis
Metabolic dysfunction–associated steatohepatitis, also known as MASH, is a condition in which fat accumulates in the liver. People with MASH can experience potentially deadly liver fibrosis. The serine protease FAP may promote this fibrosis. AstraZeneca scientists developed AZD2389, which inhibits FAP by making a covalent bond to the protein via the molecule’s nitrile.
AstraZeneca’s Anneli Nordqvist said that the campaign that led to AZD2389 began by exploring thiazolidines. Artificial intelligence played a role in helping the researchers focus their efforts. The compound is currently in Phase 2 clinical trials (NCT06750276) in people with liver fibrosis and compensated cirrhosis.
Candidate: PF-07853578
Presenter: Thomas Chappie, Pfizer
Target: 1-Acylglycerol-3-phosphate O-acyltransferase (PNPLA3) mutant I148M
Disease: Metabolic dysfunction–associated steatotic liver disease
People with PNPLA3 enzymes that carry an isoleucine-to-methionine mutation at amino acid 148 are predisposed to having higher levels of liver fat, liver inflammation, cirrhosis, and liver cancer. Studies suggest that’s because this enzyme mutant inhibits the body’s process for breaking down lipids.
Pfizer’s Thomas Chappie spoke about the company’s development of PF-07853578, which covalently binds to the PNPLA3 I148M variant via a bond made to the molecule’s carbamate group. That covalent interaction leads to removal of the disease-causing protein from lipid droplets and induces the protein’s degradation via the proteosome. PF-07853578 has completed a Phase 1 clinical trial (NCT05890105). If approved, it has the potential to be the first small-molecule therapy for this target, Chappie said.
Candidate: CK-4021586
Presenter: Luke Ashcraft, Cytokinetics
Target: Cardiac myofibrillar ATPase
Disease: Heart failure with preserved ejection fraction
Cytokinetics’ Luke Ashcraft said scientists at the company synthesized and tested more than 2,000 compounds in their search for a molecule that would bind cardiac myofibrillar ATPase, a motor protein in the heart. They think that binding this motor protein could help people who have heart failure with preserved ejection fraction (HFpEF), a disease that’s characterized by the left ventricle’s inability to relax sufficiently during the period in which the chamber fills with blood.
The company’s clinical candidate CK-4021586 features an unusual azetidine carbaldehyde. The compound is currently in Phase 2 clinical trials (NCT06793371).
Candidate: BAY 3389934
Presenter: Hartmut Beck, Bayer
Target: Coagulation factors IIa (FIIa) and Xa (FXa)
Disease: Sepsis-induced coagulopathy
When people get sepsis—a systemic response to an infection that has spread the bloodstream—they can develop a disorder that affects the blood’s clotting system. The condition is difficult to treat, and people who develop it often die. Bayer’s Hartmut Beck discussed the company’s clinical candidate BAY 3389934, an intravenously administered compound that is a dual inhibitor of two coagulation factors: FIIa and FXa. By blocking these coagulation factors, scientists may be able to alleviate the coagulopathy associated with sepsis.
Although other candidates have been developed to target these coagulation factors, most have been discontinued. BAY 3389934 is currently in Phase 1 clinical trials (NCT06854640) to assess its suitable dose and to study how it affects participants who have sepsis-induced coagulopathy.
Chemical & Engineering News
ISSN 0009-2347
Copyright © 2025 American Chemical Society
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