A protein that can suppress cell regeneration can itself be suppressed, allowing cell populations to recover from profound setbacks, such as those resulting from chemotherapy and radiotherapy. The protein, primarily expressed by neurons but recently found to be expressed by blood stem cells, is called receptor type protein tyrosine phosphatase-sigma, or PTPσ. Although it is a difficult target for drugs to hit, it can be engaged by small molecules of a class designated DJ001.
In preclinical tests, DJ001 accelerated the regeneration of blood stem cells in mice after the mice had been exposed to radiation or treated with a chemotherapeutic. DJ001 was also used to treat human blood stem cells that had been irradiated. Not only did DJ001 enable these blood stem cells to recover in lab dishes, it also promoted the survival and proper function of these same cells when they were subsequently transplanted into immune-deficient mice.
These findings, from a study conducted by scientists based at the University of California, Los Angeles (UCLA), appeared August 14 in the journal Nature Communications, in an article titled, “PTPσ inhibitors promote hematopoietic stem cell regeneration.” If the findings could be replicated in humans, they would support the idea that DJ001 could help people recover more quickly from chemotherapy, radiotherapy, and bone marrow transplants, interventions that generally suppress the activity of blood stem cells. In patients subjected to these interventions, blood and immune systems may not recover for weeks or months.
“We’re very excited about the potential medical applications of these findings,” said John Chute, MD, a physician-scientist at UCLA’s Broad Stem Cell Research Center. Particularly exciting is evidence from the study indicating that DJ001 is a selective inhibitor of PTPσ.
“DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique noncompetitive, allosteric binding,” the authors of the Nature Communications article wrote. “Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL.”
PTPσ belongs to a group of proteins called tyrosine phosphatases that are notoriously hard to block with drugs. Most tyrosine phosphatases have similar active sites—the part of the protein that interacts with other molecules to do its job. So, drugs that block the active site of one tyrosine phosphatase commonly block other tyrosine phosphatases at the same time, causing a range of side effects.
For the new study, Chute collaborated with an expert in drug development, Michael Jung, PhD, a professor of chemistry and biochemistry at UCLA. Jung’s team designed and synthesized more than 100 candidate drugs to block PTPσ; Chute and his team tested the candidates for function. Several of the candidate drugs blocked PTPσ, with no effects on other phosphatases. The strongest candidate drug turned out to be a DJ001 analog called DJ009.
“The potency of this compound in animal models was very high,” said Chute. “It accelerated the recovery of blood stem cells, white blood cells, and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”
Of the mice that received high doses of radiation, nearly all of the mice that were given DJ009 survived; more than half of those that did not receive the PTPσ inhibitor died within three weeks.
In mice that received chemotherapy—at doses approximating those used in people with cancer—mice that didn’t receive DJ009 had dangerously low levels of white blood cells and neutrophils, the cells that fight bacteria, after two weeks; in mice treated with the PTPσ inhibitor, white blood cell counts had already recovered to normal levels.
The researchers are now working to fine-tune DJ009 and other similar compounds so they can move toward human trials. They also are continuing to explore the mechanisms through which inhibiting PTPσ promotes the regeneration of blood stem cells.
“The paucity of therapeutics capable of accelerating HSC regeneration and hematopoietic reconstitution in myelosuppressed patients highlights an unmet medical need,” the authors of the current study concluded. “[Our] studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.”