Virtual meeting delivers first time drug structures

Tucked away at the end of the first week of ACS Spring 2021, a meeting of the American Chemical Society, was the always anticipated “First-Time Disclosures” session in the Division of Medicinal Chemistry, in which industry reveals the structures of its latest clinical drug candidates. The session is a rare opportunity for chemists to peek inside the medicinal chemistry industry’s process for designing and homing in on new drugs. This year’s sessions were organized by Nicole Goodwin, medicinal chemist at GlaxoSmithKline. Half of the talks in the spring 2021 session focused on the development of cancer drugs. Companies also revealed drugs targeting sickle cell disease, amyotrophic lateral sclerosis (ALS), and the rare genetic heart disease obstructive hypertrophic cardiomyopathy. This year, Goodwin pointed out that pyrazoles were popular, appearing in three out of the six candidate molecules. “Pyrazoles for the win,” she said.

Candidate: BMS-986299

Presenter: Ashvin Gavai, Senior Director, Bristol Myers Squibb

Target: NLRP3 inflammasome

Disease: Cancer

In the first talk of the first session, Gavai pointed out that drugs that enhance the activity of the T cells of the immune system are a popular way to treat cancers and work well in some patients. However, some types of tumors suppress the immune system, making T cell-targeting drugs ineffective. Instead, their research focused on a target known as the NLRP3 inflammasome pathway, a protein that can stimulate the immune system’s ability to recognize and fight tumor cells.

Based on previous research, Gavai and co-workers used imiquimod derivatives as a starting point. These are small molecules with a stable, rigid scaffold that can fit well into the target’s binding pocket. Through simulations, the group found that replacing hydrogen atoms with phenyl groups at the 7 and 8 positions of the quinoline backbone made the compound more than 100 times as potent. They synthesized the candidate BMS-986299 in 22% overall yield. Researchers injected mice with BMS-986299 and a known anticancer compound that helps the immune system kill cancer cells. In treated mice, 73% of tumors disappeared. These mice also rejected new tumor cells, suggesting that they had developed an immunological memory against the cancer. Phase 1 clinical trials are ongoing into BMS-986299 alone and in combination with the immunotherapy drugs Nivolumab and Ipilimumab for patients with solid tumors.

Candidate: JNJ-67856633

Presenter: Tianbao Lu, Research Fellow, Janssen Research and Development LLC

Target: MALT1 protease

Disease: Cancer

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) activates immune cells in humans, and keeps the immune system under control. Scientists think MALT1 protease inhibitors can be used to treat immune-sensitive cancers with certain mutations, because the proteases help activate both types of immune cells, T- and B- cells.

The group started with a series of piperidine-4-amides, and found that addition of quinolone and (trifluoromethyl)pyridine rings made the compound both effective and highly bioavailable in both mouse and rat tumors, and in some cases led to tumor stasis. JNJ-67856633 is currently in Phase 1 clinical trials alone and with Bruton’s tyrosine kinase (BTK) inhibitor, an available cancer drug.

Candidate: FTX-6058

Presenter: Ivan Efremov, Senior Director, Head of Medicinal Chemistry, Fulcrum Therapeutics

Target: EED (Embryonic Ectoderm Development) subunit of the PRC2 complex

Disease: Sickle cell disease

Sickle cell disease is caused by a mutation in the adult hemoglobin gene. Humans also make fetal hemoglobin, or HbF, at certain points in development, and HbF has been found to reduce symptoms and mortality in patients with sickle cell disease. Using CRISPR, Fulcrum scientists identified the embryonic ectoderm development protein (EED) as the regulator of HbF, and pinpointed it as a drug target.

Early on, azolopyrimidine compounds showed promise for binding to EED, but the compounds’ potency and other parameters were not ideal. The researchers then set out to make a similar macrocyclic molecule but quickly found that the synthesis was complicated and time consuming. Their final synthesis contained 16 steps, but the researchers found that these macrocyclic analogues bound EED better than the non-cyclic compounds. When the researcher looked at how their drug candidate performed in vitro, they found that FTX-6058 increased the amount of HbF by 2 to 3 fold in cell donors with and without sickle cell disease relative to untreated cells. Fulcrum is currently enrolling volunteers in a Phase 1 clinical study.

Candidate: CK-3773274

Presenter: Grace Chuang, Director, Medicinal Chemistry, Cytokinetics Inc.

Target: Cardiac myosin

Disease: Heart disease

In the last talk of the first session, Chuang spoke of Cytokinetics’ candidate treatment for the rare disease hypertrophic cardiomyopathy (HCM), an inherited condition in which the heart muscles are too weak to efficiently squeeze blood. About 1 in 3200 people develop HCM, which can result in stroke and sudden death. The surgery that can treat the disease is invasive, and existing medicines have significant side effects. Inhibiting cardiac myosin, a protein that helps control heart contraction, may allow heart muscles to properly relax, so they can pump more efficiently. A drug that inhibits cardiac myosin, mavacamten, doesn’t reach stable concentrations in people who take the drug until after about 6 weeks of treatment, which makes overdosing on the drug a concern. Cytokinetics aimed to reach the target concentration in 2 weeks, Chuang said.

Seeking a better alternative, the researchers designed molecules that fit the model of the cardiac myosin binding pocket, starting with a pyridine acetamide scaffold. They found that the R isomer of the acetamide was easier to synthesize, and that CK-3773274 showed efficacy in both small and large animals. Overall, the synthesis took 9 steps with a 36% overall yield, and the researchers can make over 500 g of the compound. In healthy volunteers, the candidate CK-3773274 reached the stable blood levels in about 14 days. Phase 2 trials are fully enrolled, and the company hopes to have data from these trials later this year.

Candidate: GDC-0134

Presenter: Michael Siu, Senior Scientist, Medicinal Chemistry, Genentech

Target: Dual leucine zipper kinase (DLK, MAP3K12)

Disease: Amyotrophic lateral sclerosis (ALS)

Coming back after the session break, Siu discussed Genentech’s work on a small molecule inhibitor to treat the neurodegenerative disease ALS, for which there are only two approved drug treatments. ALS patients usually die within 5 years of diagnosis, he said.

Because ALS drugs have to cross the blood brain barrier to reach their target, scientists have to design molecules that are below 90 Ų, and cannot include too many polar functional groups. The group screened possible molecules , selected two compounds that looked promising, and synthesized multiple variants. The researchers found that two of these candidates were able to cross the blood brain barrier in rats. In making changes to boost the potency against the DLK target, the group used a computer model to fit the structure into the binding pocket. When they tested their best candidate in a mouse model, they found that it could suppress the DLK pathway. However, the scientists needed to make the compound more lipophilic because test showed it did not penetrate well into the brain. They replaced the candidate’s ring system with a bridged morpholine ring. The researchers tested the resulting compound, GDC-0134, in a mouse model with damaged optical cells; the compound kept the cells from undergoing apoptosis. The Phase 1 study of GDC-0134 in people with ALS is finished, but the group has decided to halt clinical development. They still think DLK is a good target for ALS treatments, and Siu said that they hope to keep studying the compound as a treatment for neurodegenerative diseases.

Candidate: DCC-3014, or vimseltinib

Presenter: Timothy M. Caldwell, Principal Investigator, Deciphera Pharmaceuticals

Target: colony-stimulating factor 1 receptor (CSF1R) kinase

Disease: Cancer

In the last talk of the day, Caldwell presented a compound already known as vimseltinib as a potential cancer treatment. It targets colony-stimulating factor 1 receptor (CSF1R) kinase, which is overexpressed in several types of cancer. CSF1R signaling problems are also hallmarks of other diseases including Alzheimer’s disease and Parkinson’s disease, Caldwell said. When CSF1R is switched off, it blocks adenosine triphosphate (ATP), a cellular energy carrying molecule, from approaching the protein.

The researchers’ analysis showed that 19 H bonds formed between their drug candidate DCC-3014 and CSF1R. This holds CSF1R in a conformation that mimics the switched-off state.

In animal studies, the group saw over 70% inhibition of CSF1R even at low doses of DCC-3014.

“This is probably one of the most selective kinase inhibitors known,” Caldwell said, likely because of the high number of H bonds holding the target so tightly.

In clinical studies, researchers used DCC-3014 to treat benign tenosynovial giant cell tumors in people’s wrists, fingers, ankles and toes. Phase 1 results showed that the compound has antitumor activity. Another Phase 1/2 study is ongoing, and is currently enrolling 60 people.