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A Paragon of Structure-Based Drug Design

Jude Canon

p53 was discovered over three decades ago,1 and interest in it grew exponentially as its many roles in cellular function were uncovered. And it was thought early on once its tumor suppression function was understood that scientists would be able to modulate P53 activity or restore P53 activity to cells and that might be part of a cure for cancer. Now over 30 years later that’s proven to be much more difficult than originally thought. Targeting p53 has been elusive. It’s been a difficult target to get to.

Since the regulation by p53 is so complex, p53 itself also needs to be tightly regulated and MDM2 is one of the primary regulators of p53.2 So in tumor cells it’s thought that inactivation of p53 is an obligate step in tumor progression.

And so the cell can inactivate p53 in a variety of ways. One is by mutating p53, and in fact p53 is the most altered gene in human cancer.3 Another way p53 can be inactivated is by negatively regulating it for instance MDM2 amplification or over-expression.4

AMG 2325 is a small molecule that needs to get into tissue, get into the cell, and then get into the nucleus where p53 and MDM2 reside and then physically disrupt the interaction between MDM2 and p53.

Michael Bartberger

Computational chemistry or molecular modeling as it’s sometimes called, broadly defined means the application of mathematical and computer methods to understand structure, to understand binding of ligands, drug molecules, to their targets. In the case of the MDM2-p53 protein-protein interaction, this interaction takes place between two large biological molecules. It’s critical to be able to understand that in order to determine the structural features that the small molecule requires in order to intercept that binding event.

And what we sort of bring to the table is a 3-D, atomistic view of the structure and the binding. And it’s said that a picture is worth a thousand words, and in drug discovery that’s absolutely no different. And to be able to present, a literal atoms and bonds picture of the binding pocket adds tremendous value, I feel, to the discovery campaign. One thing that I think we do maybe a little bit differently from others in the industry is try to apply more accurate physics a little bit more numerical rigor when predicting the properties of drug-like molecules and the way they bind, the way they interact with their target.

That can be a bit more computationally expensive, a little more time-consuming, but in the long run, I think it’s been proven and MDM2- p53 is a particularly good example of this.

A precursor molecule of 232 we published in the Journal of Medicinal Chemistry,6 and gratifyingly that effort was called a paragon of structure-based design,7 I believe.

Jude Canon

Tumors that contain mutated p53 are not expected to respond to an MDM2 inhibitor like AMG 232. So we’re interested in going after tumors that have a normal functioning or wild type p53. We hope to understand if the hypothesis is correct that freeing p53, normal p53 protein, in those tumor cells and allowing p53 to resume its tumor-suppressive function will have benefit as far as anti-tumor efficacy.

References

  • 1. Crawford, L. V., et al. "Detection of a common feature in several human tumor cell lines--a 53,000-dalton protein." Proceedings of the National Academy of Sciences 78.1 (1981): 41-45.
  • 2. Prives, Carol. "Signaling to p53: breaking the MDM2–p53 circuit." Cell 95.1 (1998): 5-8.
  • 3. Vogelstein, B., S. Sur, and C. Prives. "p53: the most frequently altered gene in human cancers." Nature Education 3.9 (2010): 6.
  • 4. Rayburn, Elizabeth, et al. "MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy." Current cancer drug targets 5.1 (2005): 27-41.
  • 5. Sun, Daqing, et al. "Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2–p53 inhibitor in clinical development." Journal of medicinal chemistry 57.4 (2014): 1454-1472.
  • 6. Rew, Yosup, et al. "Structure-based design of novel inhibitors of the MDM2–p53 interaction." Journal of medicinal chemistry 55.11 (2012): 4936-4954.
  • 7. Bernard, Denzil, Yujun Zhao, and Shaomeng Wang. "AM-8553: a novel MDM2 inhibitor with a promising outlook for potential clinical development." Journal of medicinal chemistry 55.11 (2012): 4934-493

USA-CRP-126746

A Paragon of Structure-Based Drug Design

While Amgen has long been recognized for its strength in developing biologic medicines, our expertise also extends to the field of small molecule drug design. The elegant science applied to a tough cancer target exemplifies this new capability.

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One huge difference between a normal cell and a cancer cell is that normal cells know when to quit. When a normal cell suffers stress or DNA damage, regulatory proteins swing into action. If these protective proteins can’t fix the damage, they initiate a process called apoptosis, or programmed cell death.

But tumor cells keep growing and dividing despite extensive DNA damage, in large part because the key proteins that regulate normal growth have stopped working. Restoring the tumor-suppressing function to cells is a major goal in cancer therapy, and a protein called p53 could help researchers achieve that goal.

But tumor cells keep growing and dividing despite extensive DNA damage, in large part because the key proteins that regulate normal growth have stopped working. Restoring the tumor-suppressing function to cells is a major goal in cancer therapy, and a protein called p53 could help researchers achieve that goal.

“p53 has been called the guardian of the genome,”1 said Jude Canon, a principal scientist in Amgen’s Oncology Research group. ”It controls a complex network of other genes that instruct a cell how to respond to stress, and to prevent damaged cells from propagating. We believe that inactivation of p53 is a necessary step in tumor growth and progression.”

The tumor-suppressing role of p53 has been known for decades2, but efforts to translate this knowledge into new treatments have hit several barriers. In roughly half of all cancers, p53 itself has been mutated, so restoring its function with a drug would be highly problematic.

But in many other cancers, the tumor shuts down p53 by making more of a second protein called MDM2. “In a non-stressed healthy cell, MDM2 keeps p53 levels low.3 When stress is encountered, p53 signaling is up-regulated to arrest the cell’s growth so that any genomic damage can be repaired,” said Canon. “Some tumor cells are able to turn off p53 by over-expressing MDM2.”

A large job for a small molecule

In cancers where overproduction of MDM2 has disabled this p53 tumor suppressor pathway, a drug that inhibits MDM2 could restore p53 function, potentially shutting down tumor cells. Designing a drug to accomplish this task has been difficult.

The problem is that p53 and MDM2 are large proteins that operate inside a cell’s nucleus. In order to reach a target buried so deep inside a cell, a small molecule is necessary. But it’s hard to design a drug that’s sufficiently small yet able to disrupt the interaction of two large proteins.

Challenges like this are the reason that Amgen, a biotechnology company, also invests heavily in small molecule drug discovery. In the case of the MDM2 program, Amgen has invested a decade of research and made thousands of compounds in order to arrive at an MDM2 inhibitor that the team advanced into clinical trials.

The effort has been supported by a diverse team of scientists including biologists, X-ray crystallographers, medicinal chemists, and computational chemists adept in using molecular models to guide the drug design process. Amgen’s approach is distinguished by an emphasis on the relation of physics and chemistry, which can help to predict and guide the interactions between drug molecules and their target proteins.

“The chemical bonds that hold a small molecule together can rotate to give the molecule different conformations,” said Michael Bartberger, a principal scientist in Amgen’s Molecular Engineering group. “When designing a drug, you want it to assume the best conformation for the target of interest. At Amgen, we try very hard to apply our best and most rigorous physics to the conformational part of the problem. The goal is to make every atom count, either by providing a productive contact with the target protein or by predisposing the drug molecule to assume a geometry or conformation that is most congruent with the target, in this case MDM2.”

Amgen’s work in targeting MDM24 was recognized by the Journal of Medicinal Chemistry with an “Editor’s Viewpoint” cover story , describing the work as “a paragon for a structure-based approach.”5

“The techniques used and the lessons learned during the MDM2-p53 drug discovery campaign are being applied to other small molecules in Amgen’s discovery pipeline,” said Bartberger.

Amgen’s investigational MDM2 inhibitor is in early-stage clinical trials in a variety of cancers. “We are focusing on tumor types that have a high degree of normal p53 protein, or wild-type p53,” said Canon. “We hope to understand if the hypothesis is correct that freeing p53 in those tumor cells and allowing p53 to resume its tumor-suppressive function will have benefit as far as anti-tumor efficacy.”

References

  • 1. Efeyan, Alejo, and Manuel Serrano. "p53: guardian of the genome and policeman of the oncogenes." Cell cycle 6.9 (2007): 1006-1010.
  • 2. Crawford, L. V., et al. "Detection of a common feature in several human tumor cell lines--a 53,000-dalton protein." Proceedings of the National Academy of Sciences 78.1 (1981): 41-45.
  • 3. Prives, Carol. "Signaling to p53: breaking the MDM2–p53 circuit." Cell 95.1 (1998): 5-8.
  • 4. Rew, Yosup, et al. "Structure-based design of novel inhibitors of the MDM2–p53 interaction." Journal of medicinal chemistry 55.11 (2012): 4936-4954.
  • 5. Bernard, Denzil, Yujun Zhao, and Shaomeng Wang. "AM-8553: a novel MDM2 inhibitor with a promising outlook for potential clinical development." Journal of medicinal chemistry 55.11 (2012): 4934-4935.

USA-CRP-126746

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