p97 ATPase Inhibitors for Cancer and Neurodegneration

Inhibition of p97 ATPase activity triggers downstream cellular effects, including the suppression of cellular proliferation that makes cancer such a dangerous disease. And because these compounds specifically inhibit p97, they offer the possibility of treating a wide array of ailments with fewer side effects than drugs acting on broader pathways; neurodegenerative diseases, for example, display dysregulation of protein homeostasis via p97 and have the potential to be treated with these inhibitors. 

Description

Cancer cells tend to over-produce proteins, but this doesn’t generally get in the way of their growth and proliferation because these cells can rely on built-in molecular cleanup mechanisms — especially p97 ATPase — to maintain a healthy balance. Although recent evidence shows that inhibiting p97 kills cancer cells, there are currently no drugs on the market that target p97 directly. We have discovered potent and specific p97 inhibitors that may lead to new treatments for cancer, and possibly also neurodegeneration and genetic disorders involving p97 mutations. Structural analysis indicates that these compounds bind allosterically to act literally as a “wrench in the works,” blocking the motion of the p97 protein subunits.

Applications

• Treatment of cancer by suppressing cellular proliferation
• Potential treatment of other diseases that result from dysregulation of p97

Advantages

• Specifically targets p97 ATPase
• More efficacious with fewer side effects than other compounds working through similar or related mechanisms

Invention Readiness

In vivo data

IP Status

https://patents.google.com/patent/US10894782B2; https://patents.google.com/patent/WO2017197080A1; https://patents.google.com/patent/WO2018209083A1; https://patents.google.com/patent/WO2019200032A1

Related Publication(s)

Burnett, J. C., Lim, C., Peyser, B. D., Samankumara, L. P., Kovaliov, M., Colombo, R., Bulfer, S. L., LaPorte, M. G., Hermone, A. R., McGrath, C. F., Arkin, M. R., Gussio, R., Huryn, D. M., & Wipf, P. (2017). A threonine turnstile defines a dynamic amphiphilic binding motif in the AAA ATPase p97 allosteric binding site. Organic & Biomolecular Chemistry, 15(19), 4096–4114. https://doi.org/10.1039/c7ob00526a

Banerjee, S., Bartesaghi, A., Merk, A., Rao, P., Bulfer, S. L., Yan, Y., Green, N., Mroczkowski, B., Neitz, R. J., Wipf, P., Falconieri, V., Deshaies, R. J., Milne, J. L. S., Huryn, D., Arkin, M., & Subramaniam, S. (2016). 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science, 351(6275), 871–875. https://doi.org/10.1126/science.aad7974

Alverez, C., Arkin, M. R., Bulfer, S. L., Colombo, R., Kovaliov, M., LaPorte, M. G., Lim, C., Liang, M., Moore, W. J., Neitz, R. J., Yan, Y., Yue, Z., Huryn, D. M., & Wipf, P. (2015). Structure–Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97. ACS Medicinal Chemistry Letters, 6(12), 1225–1230. https://doi.org/10.1021/acsmedchemlett.5b00364

Alverez, C., Bulfer, S. L., Chakrasali, R., Chimenti, Michael. S., Deshaies, R. J., Green, N., Kelly, M., LaPorte, M. G., Lewis, T. S., Liang, M., Moore, W. J., Neitz, R. J., Peshkov, V. A., Walters, M. A., Zhang, F., Arkin, M. R., Wipf, P., & Huryn, D. M. (2015). Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway. ACS Medicinal Chemistry Letters, 7(2), 182–187. https://doi.org/10.1021/acsmedchemlett.5b00396