The Right Chemistry to Keep Going

by Anna Megdell

Rogel researchers work tirelessly, and over many decades, to develop better drug therapies for patients. Most studies never make to clinical trials. For those that do, researchers point to patience, innovation and a hefty dose of persistence.

Illustration: Erica Bass

Medication is an integral part of our lives. From over-the-counter pain relievers to daily medications to lifesaving cancer treatments, the technology and innovation imbued in drug therapies make up an essential part of society.

But how does a pill or infusion make it out of the lab to actually reach patients, beyond an idea and into a drug that is safe and effective? Rogel Cancer Center faculty doing this research range in disciplines from medicinal chemists to pharmacologists to pathologists to biologists to biomedical engineers.

This collaboration and interdisciplinary approach has led to promising discoveries at Rogel leading to the evaluation of 10 new therapeutic agents in clinical trials at this time.

But this work is "not for the faint of heart," notes Judith Sebolt-Leopold, Ph.D. Behind these successes are the many ideas that never make it out of the lab to clinical trials, and even fewer that receive FDA approval.

Sebolt-Leopold, professor of radiology and pharmacology, is co-leader of Rogel’s Developmental Therapeutics program, designed to advance basic science discoveries to the clinic. She has been in the pharmaceutical industry for decades, working at Pfizer before coming to Rogel in 2009.

"There’s a lot that can go wrong at every stage," Sebolt-Leopold says. "You need to identify the right target, and the right drug to meet that target. The goal is for the drug to be effective and safe. Once, years ago, I was working on a drug that caused amazing tumor regressions in mice. We didn’t know until we got to toxicology that that these mice were likely blind due to retinal toxicity. You put all of this work into a program, and then you get to toxicology and find something unexpected like that. And then it’s back to square one.

"When you think about all the different things that can go wrong, getting a compound all the way through advanced preclinical testing and clinical trials is a brutal business," she continues. "The failure rate of oncology drug candidates entering early clinical trials is quite high. Less than 5% of oncology clinical leads ultimately receive regulatory approval".

Given the multitude of variables at every stage of the process, what differentiates those ideas that stall from those that progress? Here, Rogel researchers discuss their research and the persistence, rigor and creativity that keeps it going.

Reaching Patients

Illustration: Erica Bass

Most recently, Sebolt-Leopold’s research has focused on the molecule MTX-531, a kinase inhibitor that selectively impairs signaling mediated by two key drivers of cancer therapy resistance: epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-OH kinase (PI3K).

"By dual targeting of EGFR and PI3K, MTX-531 acts to shut down the escape mechanisms that tumors use to resist treatment. In certain cancers, such as head and neck squamous cell carcinomas, each of these kinases is known to mediate resistance to inhibition of the other," Sebolt-Leopold says.

In preclinical testing, MTX-531 led to tumor regressions in multiple head and neck cancer models and was well tolerated. In combination with drugs targeting the RAS pathway, MTX-531 was shown to be highly effective against KRAS-mutated gastrointestinal tumors originating in the colon or pancreas.

Other PI3K inhibitors are associated with hyperglycemia, which can be severe enough that treatment must be stopped, but MTX-531 doesn't lead to this side effect in mice, indicating it could become a less-toxic treatment option. The team is now investigating the toxicology of the molecule, with the hope of initiating clinical trials in patients later this year.

Sebolt-Leopold’s work with kinase inhibitors began over 20 years ago when she worked in drug development at Pfizer. The innovative design of MTX-531 was achieved through a computational chemistry approach, led by Sebolt-Leopold and Christopher Whitehead, Ph.D., a former member of the Sebolt-Leopold laboratory team, and currently chief operating officer of MEKanistic Therapeutics, Inc. Sebolt-Leopold, with Whitehead, co-founded MEKanistic Therapeutics, Inc., a U-M spinoff, and has equity in the company.

Sebolt-Leopold says that MTX-531 is a demonstration of a continued commitment to advancing cancer research by discovering and advancing first-in-class therapeutics. "When working on unprecedented approaches, you’re attempting to solve a problem that no one has ever solved. Your knowledge of the biology is inherently incomplete, increasing the likelihood of unknown pitfalls that must be discovered and managed. However, while the risks of first-in-class lead molecules are inherently higher, so are the potential rewards when these programs are successful.

"In drug company laboratories, one often does not have the opportunity to model clinical applications of lead candidates in detail," said Sebolt-Leopold. "At Rogel, I have the unique opportunity to extend my research on molecularly targeted agents to a more translational level."

The long-haul nature of this research is characteristic of all drug development, Sebolt-Leopold says.

"During the pandemic, we identified a flaw in an earlier lead we’d been cultivating for a long time. We’d gone into early safety testing and we had to figure out another option to keep the program moving forward. MTX-531 is what came out of that pivot. That was in 2020. That’s how long it takes to get from the drug screening stage to toxicology testing, where we are now.” Sebolt-Leopold feels optimistic and grateful that her and her team’s persistence seems to be paying off.

"While it's really exciting when your drug goes into patients, we must remember that despite the advances in cancer treatment over the past couple of decades, we still have a long way to go, especially for those who have exhausted all available therapy options. We must never forget that these patients are waiting for the next available treatment. That's what motivates me."

‘We didn’t expect it to get this far’

Jolanta Grembecka, Ph.D., professor of pathology, is co-leader of the Developmental Therapeutics program with Sebolt-Leopold. Grembecka, along with collaborator Tomasz Cierpicki, Ph.D., professor of pathology, works on several targets relevant to acute myeloid leukemia, including development of menin inhibitors. "The menin inhibitor project started 15 years ago when I first arrived at the University of Michigan," Grembecka says. "There were no small molecule inhibitors when we started this project."

Grembecka and Cierpicki performed high throughput screening at the U-M Center for Chemical Genomics to identify initial small molecules targeting menin. Over the next five years, the team used medicinal chemistry to optimize the compounds they identified and structural biology to characterize how the compounds interacted with the target. Finally, they identified molecules which, in preclinical models, were able to block leukemia progression.

In 2015, after preclinical development at Rogel, Grembecka’s and Cierpicki’s teams partnered with the biotechnology company Kura Oncology to translate their findings to the clinic. Over the course of three years, they collaborated with industry scientists to identify menin inhibitor called KO-539 (ziftomenib) that could be translated to a clinical study. In 2019, a phase 1 multi-institutional clinical trial in AML patients was initiated with ziftomenib, and, in 2022, the phase 1 was completed and moved to phase 2.

Now, the enrollment portion of that trial has concluded and Grembecka is awaiting the results. "The next step is to file a drug application by Kura Oncology with the FDA. But it’s a very advanced program. It’s a major accomplishment in terms of pioneering the development of menin inhibitors," she says.

This milestone makes the last 15 years worth it. "When we started this project, we didn’t expect it would go so far. It’s extremely rewarding and highly inspiring to continue our research devoted to developing new therapeutics. It’s a long story. But it started from nothing and now we’re here."

Though the successes of a project like this can be encapsulated in bullet points, Sebolt-Leopold is quick to point out just how rare it is to evolve a novel concept into a safe, efficacious therapy.

"Making the right decisions extends beyond target and drug selection. Designing the right mouse trials is also critical. It's not always apparent which preclinical models are going to benefit the most from a given molecularly targeted agent because of tumor heterogeneity," she says. "And even when you test the right models, you need to be using clinically relevant endpoints. A lot of companies will advance cancer drugs into developmental candidates because they reduce tumor growth rate in mice, but not to the degree required to cause regressions, or even tumor stasis. There’s a need for very stringent preclinical testing that incorporates clinically relevant endpoints."

Grembecka agrees. "You have to be very, very rigorous to be absolutely sure that what you’re developing makes sense," she says. "It’s underestimated how much is required to advance a clinical candidate compound. It doesn’t happen often in academia. You develop hundreds or even thousands of analogs sometimes and have to test all of them thoroughly to ensure you’re selecting the best possible compound to advance. In our case, we didn’t move forward with the compound we identified first. We had a collection of them to identify the molecule that had the best activity and properties for clinical translation.

"It’s a lot of effort and a lot of dedication," she continues. "But overall, especially if you see a positive outcome in patients, it’s totally rewarding.

Drug Hunters

For Nouri Neamati, Ph.D., the close collaboration in academic drug discovery sets the research apart. "All of our labs across 10 departments are in one building for the purpose of working together. It’s a multidisciplinary approach. We need to have all of the components, the whole package, to make progress. Most academic labs can’t do that, but we have core facilities that enable us to work really closely," he says. "We have all different backgrounds, but we’re all drug hunters."

Neamati, John G. Searle Professor of Medicinal Chemistry, works on the preclinical stage of small molecule drugs, identifying novel compounds with novel mechanisms of action. He uses machine learning to comb through libraries of encoded DNA to identify small molecules that could bind to novel targets.

Lately, his research has focused on developing a drug to target mitochondria, the part of the cell that produces energy. "It turns out that cancer stem cells and other cancer cells that become resistant to drugs are highly dependent on the mitochondria," Neamati explains.

The hope is that by targeting this specific part of a cell, the drug-resistant cells can be selectively targeted. Studies have shown that people who take metformin, a drug used to treat diabetes, have less chance of developing prostate or breast cancer. "Nobody knows exactly why, but we think it has to do with the mitochondria," Neamati says. "The problem with metformin is it has a very short half-life. It’s not potent enough to block cancer. Now, we are designing novel compounds with similar mechanism to see if we can develop something that is more potent against cancer, but is also safe and efficacious."

Neamati sees drug discovery becoming more dependent on machine learning. Still, he adds that despite this technology, the process of creating drugs that are viable in the long term will always require grit, persistence and time. "Machine learning is an amazing tool but, at the end of the day, it’s still just a tool. You can use all the technology in the world, but you still need to polish your compound, test it with independent labs to avoid biases, make it better. It’s the researchers who optimize the design."

This rigorous process thrives in an academic research setting, where faculty from numerous disciplines are inspired to share ideas.

Neamati reflects on where his passion for developing small molecule drugs began. "I was a student at the MD Anderson Cancer Center where we shared a cafeteria with patients. I saw patients everyday and I remember thinking, ‘I have to do something to help them.’ An awareness of the patient has always stayed with me. It’s important for us as basic scientists to understand their experience. That’s why we do this."

Continue reading the 2025 issue of Illuminate.