Weill Cornell inhibitor selectively blocks TNKS2 and slows TNKS1-deficient cancer cells in vitro
A compound inhibiting TNKS2 about 30 times more than TNKS1 suppressed growth of cancer cells lacking TNKS1 in lab dishes, with no effect on cells with normal TNKS1.
Researchers led by Weill Cornell Medicine have described a genetic vulnerability shared by many WNT-driven cancers and developed a compound that exploits it, according to eurekalert.org. The study appeared on Nov. 2 in Nature Chemical Biology. The work is at an early preclinical stage, and the compound was tested in cell culture. eurekalert.org
eurekalert.orgeurekalert.orgOpen source ↗
The senior author is Dr. Lukas Dow, professor of biochemistry in medicine and a member of the Sandra and Edward Meyer Cancer Center. The first author, Dr. Jill Zimmerman, was a doctoral student in the Dow Lab during the study.
A paired-enzyme weakness in WNT-driven tumors
Hyperactivity of the WNT pathway is seen in almost all colorectal cancers, more than half of breast cancers, and substantial proportions of liver, lung, prostate, skin, bone and gynecologic cancers. Suppressing WNT signaling without harming normal cells has been notoriously difficult. One approach targeted the two WNT-supporting tankyrase enzymes, TNKS1 and TNKS2, but inhibiting both can harm healthy cells, and experimental tankyrase inhibitors had dose-limiting side effects in initial clinical trials.
The team found that in some cancer cells, knocking down TNKS2 alone was enough to affect WNT signaling. Most cancers undergo large-scale DNA deletions, and one of the most common of these removes the gene for TNKS1. This does not harm the cancer cell, since TNKS2 serves the same function. It does leave the cell dependent on TNKS2, so a drug inhibiting only TNKS2 could hobble or kill such cells while sparing healthy cells that contain TNKS1. eurekalert.org
eurekalert.orgeurekalert.orgOpen source ↗ The researchers confirmed the concept by suppressing TNKS2 selectively with genetic techniques.
Designing a selective inhibitor
Making a TNKS2 inhibitor with little effect on TNKS1 was difficult because the active sites of the two enzymes are virtually identical. With computational and medicinal chemists, the team based its design on the slightly different structures of the enzymes. Screening compounds made by this strategy yielded one that inhibits TNKS2 about 30 times more than TNKS1.
In lab dish tests, the compound suppressed the growth of cancer cells with partial or full TNKS1 loss. It did not affect the growth of cells with a normal amount of TNKS1.
The group now aims to develop a next-generation compound with better drug-like properties, using detailed structural models of TNKS1 and TNKS2 built late in the study. If such a compound performs well in full preclinical tests, the researchers hope to take it into clinical trials. eurekalert.org
eurekalert.orgeurekalert.orgOpen source ↗ "There's still a lot of work to be done, but so far this looks like a rare example of being able to use tumor cells' genetics to target them while sparing normal cells," Dow said.
