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ACS Meeting News

Hybrid meeting divulges structures of drug candidates

Industry chemists presented potential treatments for diseases including cancer and Alzheimer’s

by Leigh Krietsch Boerner
March 25, 2022


Popping up midweek at the ACS Spring 2022 meeting, the crowd-favorite session “First-Time Disclosures” gave attendees an uncommon peek at drug candidates the medicinal chemistry industry has been working on. Cancer targets proved to be a focus for many companies, as usual: three out of the six companies presented potential cancer therapies. Scientists also revealed drugs to treat Alzheimer’s disease, inflammatory skin disorders, and hereditary angioedema, a rare disease that causes swelling in the body. Session organizer Nicole Goodwin from GlaxoSmithKline called the session, which was organized by the Division of Medicinal Chemistry, “an excellent array of programs across all different therapeutic areas showcasing novel and high-profile targets in the industry.” She also noted that all these companies progressed their research despite the many setbacks the pharmaceutical industry has had to deal with during the COVID-19 pandemic. Here are the drug candidates presented at the session.

Chemical structure of LY3372689.

Candidate: LY3372689

Presenter: Dustin Mergott, Eli Lilly and Company

Target: O-GlcNAcase enzyme

Disease: Alzheimer’s disease

Dustin Mergott delved into the inner workings of how Alzheimer’s disease affects the brain. There are about 40 million people living with the disease worldwide , Mergott said. In the disorder, tau proteins, responsible for keeping the ends of neurons stable, aggregate and damage neuron function. The O-GlcNAcase (OGA) enzyme removes a glycose from the tau protein, making the protein more susceptible to aggregation. Mergott’s team at Eli Lilly and Company found that blocking OGA in mouse models slowed the aggregation of tau proteins by 50%. The researchers sought their top candidate by starting with several small molecules that fit into the binding pocket of OGA and reduce tau aggregation.

Through examining crystal structures of the different compounds bound to the OGA protein, the group discovered that substituting carbon atoms for heteroatoms, adding fluorines, and jiggering the structure to make the protein close around the compound all contributed to longer and stronger binding. The group eventually homed in on the compound it calls LY3372689, which stayed in the OGA enzyme for 14 days after a 1 mg dose and showed minor adverse effects in early clinical trials. The compound is currently in a Phase 2 clinical trial, and the team expects results in June 2024, Mergott said.

Chemical structure of AZD9574.

Candidate: AZD9574

Presenter: Jeffrey Johannes, AstraZeneca

Target: Poly(ADP-ribose) polymerase 1

Disease: Cancer

The poly(ADP-ribose) polymerase (PARP) enzyme family is involved in DNA damage and repair. Blocking two closely related enzymes from this family, PARP-1 and PARP-2, results in double-stranded breaks in DNA that the cell must repair before it can divide. Cancer cells are worse at repairing these breaks than healthy cells, so targeting PARP as a cancer therapy leads to the selective death of tumor cells, Jeffrey Johannes said. In 2021, AstraZeneca developed a small-molecule PARP inhibitor called AZD5305, but this compound did not enter the central nervous system (CNS) efficiently.

The group examined crystal structures of AZD5305 bound to both PARP-1 and PARP-2, then created several small molecules that mimic this binding pattern. The researchers found that compounds with an all-carbon core bound to the target enzymes best, but subbing a nitrogen in the main ring let the molecule slip into the CNS more easily. Removing a carboxamide side group also gave better CNS penetration, but deleting this polar group created off-target effects. The team eventually found that putting an amine group next to a fluorine was the sweet spot: the molecule is potent, hits the right target, and is able to get into the CNS. When the researchers injected two different doses of this compound, AZD9574, into a mouse model, it was effective at reducing tumor size for more than 155 days without substantial toxicity. AZD9574 will soon enter Phase 1 clinical trials, Johannes said.

Candidate: PF-07038124

Chemical structure of PF-07038124.

Presenter: David Limburg, Pfizer

Target: Phosphodiesterase 4

Disease: Inflammatory skin conditions

Atopic dermatitis and psoriasis are chronic, inflammatory skin disorders. To treat these, scientists often target phosphodiesterase 4 (PDE4) because blocking this enzyme dampens the body’s inflammatory response. The topical drug crisaborole (Eucrisa) is an effective PDE4 inhibitor used to treat these conditions. Pfizer scientists wanted to combine a PDE4 inhibitor with newer antibody therapies that can also treat these skin conditions to make a next-generation topical drug, David Limburg said. The group looked to incorporate boron into its compound because the element can make stable bonds adopt a tetrahedral shape. This shape binds well to biological nucleophiles and would allow the team to link the molecule to the antibody treatment.

Using crisaborole as their model, the researchers created a compound containing an oxaborole ring, a chiral center, a catechol, and an N-heterocyclic core. This compound, PF-07038124, is an effective PDE4 inhibitor and worked well in models but is tricky to make, Limburg said. After a few false starts, the team ended up using a ferrocene compound to catalyze the synthesis. This method allowed the group to make kilogram quantities of the compound with good yields and specificity. PF-07038124 has gone through both Phase 1 and 2A clinical studies, and a Phase 2B study is scheduled for later this year.

Chemical structure of AMG 650.

Candidate: AMG 650

Presenter: Nuria Tamayo, Amgen

Target: Kinesin family member 18A

Disease: Chromosomally unstable cancers

Chromosomally unstable cancers can happen when cells don’t separate chromosomes properly during division. This misstep results in daughter cells with missing or extra partial or whole chromosomes. Kinesins are a family of molecular motors that do this separation step. Inhibiting these proteins can shut down cell division in tumors, so scientists are targeting kinesins as a cancer treatment. Nuria Tamayo and her group at Amgen are looking for a drug that inhibits kinesin family member 18A (KIF18A). One known inhibitor of KIF18A triggered cell death during mitosis, but it isn’t a feasible clinical candidate.

The team looked at a library of analogs of this compound and after multiple modifications developed a compound that had high activity against cancer cells, stayed in cells long enough to be effective, and could be taken orally. The compound, AMG 650, is currently in a Phase 1 clinical study.

Chemical structure of BLU-945.

Candidate: BLU-945

Presenter: Thomas Dineen, Blueprint Medicines

Target: Epidermal growth factor receptor

Disease: Treatment-resistant non-small-cell lung cancer

One way to treat cancer is to target the epidermal growth factor receptor (EGFR), a protein on the surface of cells that helps control cell growth. EGFR-inhibitor treatments for non-small-cell lung cancer exist, but many cancers eventually develop resistance to these, usually through the accumulation of mutations in EGFR, Thomas Dineen said. There are treatments for tumors with double mutations in EGFR, but none for people with triple mutations.

Through modifications to make their structure sit better in the binding pocket, such as adding side F and CH3 groups, Blueprint Medicines researchers were able to increase potency against triple mutants. Adding a sulfone and changing the core of the compound allowed the team to reduce unwanted chemical side reactions. BLU-945 was effective against patient-derived triple-mutant cancer cells and worked even better when given with osimertinib, another cancer treatment.

Chemical structure of KVD900.

Candidate: KVD900

Presenter: Rebecca Davie, KalVista Pharmaceuticals

Target: Plasma kallikrein

Disease: Hereditary angioedema

The rare disease hereditary angioedema causes painful swelling and is sometimes fatal, particularly when it affects the throat and intestines. Existing treatments target plasma kallikrein (PKa), an enzyme that releases bradykinin, which causes inflammation. Injectable PKa inhibitors have been shown to be safe, but there are no oral drugs that people can take in immediate reaction to an acute swelling event. To make a PKa inhibitor that can be absorbed when taken by mouth, the compound needs to contain a weakly basic chemical group on the rightmost side of the molecule, Rebecca Davie said.

The team synthesized a collection of compounds that had various five-membered rings in the core of the molecule and assorted amines at the rightmost side, then tested these in rat models to see what combination bound to PKa the best. The group found that adding a chlorine atom increased the potency and selectivity of the compound. The compound was safe, well tolerated, and effective in a Phase 2 clinical trial, Davie said, and a Phase 3 trial is underway.


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