In the early 2000s, Judy Sebolt-Leopold led a team of scientists at Parke-Davis who became the first to show that the rat sarcoma-mitogen-activated protein kinase (Ras-MAPK) pathway — a signaling cascade crucial in the regulation of the cell cycle and cell growth — is a druggable target to treat cancer (1). Their team developed the very first oral mitogen-activated protein kinase kinase (MEK) inhibitor that advanced into clinical trials (2). MEK inhibitors prevent activation of the Ras-MAPK pathway, which helps tumor cells proliferate and survive.

Sebolt-Leopold, a cancer biologist now at the University of Michigan, considered retiring after Pfizer acquired Parke-Davis and shut down their Ann Arbor branch in 2007 — but ultimately, she decided against it. Instead, Sebolt-Leopold started up her new lab at the University of Michigan in 2009, and in 2015 founded a new biotech company with Christopher Whitehead, a computational chemist who she had worked with at Pfizer. They named their new company MEKanistic Therapeutics after their interest in developing drugs that would augment the effectiveness of MEK inhibitors.

Today, their lead compound, MTX-531, has so far shown promise in preclinical cancer models. It is the first single molecule that selectively targets two kinases at once: epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-OH kinase (PI3K). These are both oncogenic kinases that contribute to tumorigenesis, and scientists have found that head and neck cancer cells commonly display adaptive resistance mechanisms to kinase inhibitor therapies when one of them is inhibited, but not the other (3,4). Yet, when clinicians prescribe multiple drugs at once to block these signaling pathways, toxicity increases to the point where patients cannot tolerate the medications.

As a single drug that inhibits EGFR and PI3K simultaneously, Sebolt-Leopold and her team were surprised to find that MTX-531 could be the solution to the toxicity problem. Using patient-derived xenografts (PDX) mouse models of colorectal and head and neck cancers, Sebolt-Leopold’s team at MEKanistic Therapeutics found that MTX-531 selectively targeted EGFR and PI3K to successfully treat tumors without toxic side effects (5). They have plans to start a clinical trial with MTX-531 by the end of 2025.

“When it comes to the mouse data, this drug is about as good as it gets. With all my years at Parke-Davis/Pfizer, I've never seen a drug molecule this active in tumor-bearing animals,” said Sebolt-Leopold.

Why did your team decide to design a dual-hit kinase inhibitor?

When I entered academia, I wanted to find a way to make MEK inhibitors more effective against Kirsten rat sarcoma (KRAS) mutant tumors. By that time, we had a better appreciation for the role of EGFR and PI3K in activating the Ras-MAPK pathway in these tumors. So, we thought, what if we could design a molecule that would inhibit both of these adaptive resistance mechanisms?

At that point in my career, I didn't have access to the quite large chemical libraries found in drug companies. The use of computational drug design allowed us to rationally design something that, on purpose, hits the two key targets that we wanted — because combination therapy, in almost all cases, is what patients are going to need. With only one molecule, we only have to optimize one profile, and we’re not liable to as many drug-drug interactions. Of course, the key questions we need to now answer are, is it selective, and is it well tolerated?

To design MTX-531, my colleague Chris Whitehead studied the way that known EGFR and PI3K inhibitors interact at the adenosine triphosphate (ATP) site of a kinase. Basically, he found that MTX-531 binds to one kinase in one conformation, and then the molecule can flip around and bind to the other kinase. It's what he calls: “flipped binding mode.”

What is the biggest advantage of MTX-531 compared to other therapies?

To the best of my knowledge, there is no direct comparison because there are no other dual molecules like MTX-531. But compared to the pan PI3K inhibitors, MTX-531 did not cause the usual toxic hyperglycemia in mice. This is a side effect that commonly happens with other PI3K inhibitors because they lead to elevated insulin levels, resulting in insulin-mediated reactivation signaling. Because MTX-531 doesn’t activate this pathway, it's going to translate into a huge advantage — not just for toxicity, but for efficacy too. We’re shooting ourselves in in the foot with respect to efficacy if we can't effectively shut down that pathway.

The PI3K inhibitors have earned their reputations as drugs with severe side effects. But whether it's us or somebody else, the field has to find a way of targeting it because it is a central survival pathway in tumor cells. Ras-MAPK was considered the holy grail for a long time, but it’s been shown to be druggable now. I think PI3K is the next holy grail in the field. I am excited about at least taking this approach forward and seeing whether we can show once and for all that it’s druggable in solid tumors.

What has your preclinical data shown so far with MTX-531?

In head and neck human cancer cell lines that we implanted into mice, we saw complete regression of the tumor across a range of doses. We could dose mice daily for as long as 300 days, and the animals continued to thrive and showed no signs of their tumor coming back. In our PDX studies where we implanted tumor tissues directly into mice, we had an exceptional responder model where 50 percent of the mice had complete and durable regressions. There were other models with more variable responses, but we saw tumor regressions in some mice in each of the five models we studied.

What are your next steps to move MTX-531 to the clinic?

We completed the in-life portion of pivotal toxicology studies and are waiting for the final reports. We are preparing material for the Investigational New Drug (IND) paperwork, which we anticipate filing by mid-2025. We're busy planning what the clinical trials will look like and talking to advisors now.

What do you personally find the most exciting about working on this drug?

It’s all about patient impact. We had a mantra at Parke-Davis: “The patient is waiting.” I remember how satisfying it was with the MEK inhibitor to see the clinical trials start, listen in on the clinical calls from different sites, and hear how this one patient did particularly well. There is no better high than that because that's actually what we're in it for. I want to experience that.

However, I’ve been in the field for a long time, and I understand what the odds are. For any one program, they're against us from the beginning. However, I do think companies need to take more risks. It does bother me that the oncology field as a whole doesn't take risks. There are too many times when one company shows that we can do something, and then all these other companies swarm in and they do the same thing. They say, "Well, we weren't going to be first-in-class, so we’ll be best-in-class." But when we think about how all those resources are going to the same thing, when all these patients are dying of cancer — that's not the kind of science I want to do. I’m doing first-in-class. I'll go out the way I came with the first-in-class MEK inhibitors we developed at Parke-Davis. I will walk the talk.

This interview has been condensed and edited for clarity.

References

1. Sebolt-Leopold, J.S. MEK Inhibitors: A Therapeutic Approach to Targeting the Ras-MAP Kinase Pathway in Tumors. Curr Pharm Des  10, 1907–1914
2. LoRusso, P.M. et al. Phase I and Pharmacodynamic Study of the Oral MEK Inhibitor CI-1040 in Patients With Advanced Malignancies. J Clin Oncol  23, 5281–5293 (2005).
3.  Elkabets, M. et al. AXL Mediates Resistance to PI3Kα Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas. Cancer Cell  27, 533–546 (2015).
4. D’Amato, V. et al. The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models. Br J Cancer  110, 2887–2895 (2014).
5. Whitehead, C.E. et al. A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance. Nat Cancer  5, 1250–1266 (2024).