A team of scientists led by the University of Michigan Rogel Cancer Center and Case Comprehensive Cancer Center has identified the binding site where drug compounds could activate a key braking mechanism against the runaway growth of many types of cancer. The discovery marks a critical step toward developing a potential new class of anti-cancer drugs that enhance the activity of a prevalent family of tumor suppressor proteins called protein phosphatases. The study was led by first authors Daniel Leonard, an MD and PhD student and member of Dr. Narla’s lab when the research was at Case Western Reserve and the Case Comprehensive Cancer Center, and research scientist Wei Huang, PhD, of the Taylor lab. The research required a marriage of scientific disciplines and areas of expertise, notes co-senior author Goutham Narla, MD, PhD, chief of the division of Genetic Medicine in the Department of Internal Medicine at the U-M Medical School. There has been a lot of activity and excitement in recent years around the development of kinase inhibitors — small molecule compounds that go after the protein kinases whose dysfunction is involved in the explosive growth and proliferation of cancer cells. That is, turning off cancer’s “on switch”.
The new research attacks cancer from the opposite side of the equation, turning on cancer’s “off switch” by stabilizing protein phosphatases whose malfunction removes a key brake on cancer growth. Scientists have known for a while that certain molecules were capable of increasing the activity of the tumor suppressor protein PP2A, killing cancer cells and shrinking tumors in cell lines and animal models — but without information about the physical site where the molecules interact with the protein, trying to optimize their properties to turn them into actual drugs would require endless trial and error. Protein phosphatase 2A is an enzyme that works in the opposite way to protein kinases, that is, it detaches phosphate residues from the proteins put by the kinases themselves. This phosphorylation-dephosphorylation mechanism is present in every living cell. Thousands of cellular proteins go through this process every moment inside the cells. Aside from regular enzymes in the metabolism of glucose, fat, cholesterol and other cellular reactions, this “phospho-dephospho” mechanism turns on and off many components that cells use to complete their duplication. Among these, the mitogenic protein kinases (MAPKs, CDKs, Plks, etc.) that trigger DNA synthesis.
MAPKs are activated by growth factors that stimulate both normal and tumor cells to duplicate. But while normal cells know when to put a brake on the process, by activating phosphatases including PP2A, in cancer cells this mechanism is poorly controlled. PP2A itself may be subject to mutations which make it partially lose its suppressive function. And so it can become an oncogene and promote the appearance of tumors. Some natural carcinogens, indeed, are tumor promoters because they block PP2A. They are produced mostly from vegetable or microorganism sources and often thety are toxins, such as cantharidin, microcystin or okadaic acid. But so far no substances known to directly activate this enzyme are known to man. This made him “unattainable” for a long time in the treatment of tumors, despite the desire to find drugs to control his activity. This may be the right time: Dr. Narla’s team identified a polycyclic nitrogen molecule in a screening of several thousand, which met the requirements to slip into a PP2A pocket with no apparent biological function. Through crystallography and computer modeling analysis (QSAR), the group obtained the desired molecular model.
Co-senior author Derek Taylor, PhD, an associate professor of Pharmacology and Biochemistry at Case Western Reserve University and member of the Case Comprehensive Cancer Center, explained the work: “We used cryo-electron microscopy to obtain three-dimensional images of our tool-molecule, DT-061, bound to PP2A. This allowed us to see for the first time precisely how different parts of the protein were brought together and stabilized by the compound. And if we were just activating PP2A, killing cancer cells and slowing the growth of cancer without the structural data — that would be a really nice half-story as well. But working together, we now have a story about being able to drug this previously undruggable tumor suppressor. We can now use that information to start developing compounds that could achieve the desired profile, specificity and potency to potentially translate to the clinic.” In the paper, the researchers speculate how a combination of both approaches simultaneously might offer an even more powerful one-two punch — potentially helping to overcome cancer’s ability to evolve to thwart a singular approach. The researchers propose calling this class of molecules SMAPs — for small molecule activators of PP2A.
Along with cancer, PP2A is also dysregulated in a number of other diseases including cardiovascular and neurodegenerative diseases. And the researchers are optimistic the findings could also open opportunities to develop new medicines against diseases like heart failure and Alzheimer’s as well.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Alzahrani R et al. J Cancer Prev. 2020 Mar 30; 25(1):21-26.
Wei H, Zhang HL et al. Neurotherapeutics. 2020 Feb 24.
Farrington CC et al. J Biol Chem. 2020 Jan; 295(3):757-770.
O’Connor CM et al., Narla G. Oncogene 2020; 39(3):703.
Dott. Gianfrancesco Cormaci
Ultimi post di Dott. Gianfrancesco Cormaci (vedi tutti)
- Extracellular ves(h)icles for tumoral detection: upgrades in biotech for early liver cancer diagnosis - Agosto 5, 2022
- Transglutaminasi 2: l’enzima della malattia celiaca che fa il mutaforma nella sclerosi multipla - Agosto 5, 2022
- Vaccinazioni contro influenza ed herpes: perchè proteggono dall’attacco del COVID? - Agosto 5, 2022
- I nuovi vaccini contro la Omicron: il “banale” coronavirus si sta trasformando in un’influenza? - Agosto 4, 2022
- Il ruolo delle proteine S100 nella psoriasi: sulle strade per capirle e su come bloccarle - Agosto 4, 2022