Lin BioScience has licensed the intellectual property portfolio for a novel inhibitor of CDC7 kinase. Under this worldwide exclusive licensing agreement with Columbia University and Memorial Sloan Kettering Cancer Center, Lin BioScience plans to develop this potent CDC7 inhibitor (LBS-007) against a wide range of cancers.
CDC7 is one of two heterodimeric kinases involved in the cell cycle regulation of eukaryotic DNA replication. Activated at the G1/S phase transition, CDC7 activates the helicase that unwinds DNA in preparation for cellular DNA replication. CDC7 is overexpressed in cancer cells, and its inhibition leads to irreparable DNA damage and apoptosis. In normal cells, however, CDC7 inhibition harmlessly stalls the cell cycle, which restarts when levels normalize. This selectivity has made CDC7 a sought-after target for drug makers.
For Mark Frattini, M.D, Ph.D., Associate Professor of Medicine and Experimental Therapeutics at Columbia University Medical Center (CUMC) and Director of Research for the medical center’s Hematologic Malignancies, the licensing of LBS-007, which he developed in collaboration with researchers at Memorial Sloan Kettering Cancer Center, is the culmination of almost a decade of work developing a unique CDC7 inhibitor that is less prone to off-target effects and shows preclinical effectiveness against nearly 80 malignancies, ranging from leukemia and non-small cell lung cancer to melanoma and ovarian cancer.
"CDC7 inhibitors are a new class of anti-cancer therapy, and Lin BioScience is proud to be working with Dr. Mark Frattini and his team at Columbia University, who are leading experts and among the first to develop this novel drug treatment. LBS-007 has shown its potential as a potent agent to treat a variety of cancer indications, and we look forward to initiating a first-in-human Phase 1 trial in 2017,” said Dr. Tom Lin, CEO of Lin Bioscience.
Frattini and his collaborators initially focused on hematologic cancers, and have shown strong results of tests on primary patient samples and animal models of multiple hematologic cancers. The first-in-human Phase 1 trial will begin this year in patients with relapsed or refractory acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia in blast crisis and resistant to oral tyrosine kinase inhibitors, and myelodysplastic syndrome.
About Lin BioScience
Lin BioScience, Inc. is a new drug development company that specializes in the development of innovative drug treatments for diseases with unmet medical needs. Lin BioScience's diverse and novel pipeline consist of first-in-class drugs aimed to treat life-threatening or disabling diseases in Oncology, Ophthalmology, and Cardiovascular indications.
A Conversation with Mark Frattini, M.D., Ph.D., Associate Professor of Medicine and Experimental Therapeutics at CUMC and Director of Research, Hematologic Malignancies, Columbia University Medical Center.
CTV: You’ve been working on this concept for a CDC7 inhibitor for more than 10 years. What piqued your interest in CDC7?
MF: I’ve been thinking about CDC7 as a novel target for cancer therapy since I was at Memorial Sloan Kettering Cancer Center, starting in 2002. I worked with Dr. Thomas Kelly, who was a pioneer in the area of DNA replication, and he was the first person to develop an in vitro DNA replication system back in the 1980s, which led to the discovery of many of the different proteins involved in the initiation and elongation phases of DNA replication. This is an area I’ve always been interested in, and once I decided to go into oncology, I began to think about this particular human enzyme, CDC7, as a potential target for cancer therapy.
CTV: How is CDC7 implicated in cancer?
MF: CDC7 is a kinase involved in the cell cycle regulation of eukaryotic DNA replication. It gets turned on at the end of G1, and is active through S phase. It essentially sets up the cell to begin replicating its DNA. CDC7 is what activates the helicase that begins to unwind the two strands of DNA so that replication can take place. This kinase is active in all cells that are growing, but in cancer cells, it is almost always overexpressed, and that’s why it’s a drug target.
CTV: What happens when CDC7 is inhibited in cancer cells?
MF: This is part of why this kinase is so interesting—in the laboratory, when we inhibit CDC7 in cancer cells, it causes a tremendous increase double stranded DNA breaks. The replication fork collapses, and the cell can no longer complete S phase. Apoptotic cell death is triggered, and the cancer cells die. But in normal cells, inhibition of CDC7 brings S phase to a halt until DNA damage can be repaired, then the cycle resumes and the cell can continue normal growth patterns and growth control mechanisms. When CDC7 is inhibited, cancer cells die, but normal cells don’t. In animal studies, we’ve seen that our compound is nontoxic to normal cells at levels where the cancer cells are killed. In mouse models, for example, we can eradicate cancer, and the mice are otherwise healthy. It’s very selective for cancer.
CTV: The compound you’ve developed isn’t the first to attempt to inhibit CDC7. How is it different?
MF: This compound is unique in several ways. Most kinase inhibitors are synthetic, and this is actually the product of a bacteria. It’s also an allosteric inhibitor rather than an ATP mimetic, and the reason that’s important is that kinase inhibitors that bind to a kinase like ATP does tend to produce a lot of off-target effects, which we haven’t seen in our testing. We can use this compound very efficaciously at low doses, and we can see that it affects cancer more than normal cells.
CTV: What’s the next step in terms of human trials?
MF: I’m a leukemia physician, so it has been a priority of mine to bring this back to the clinic. Thanks to our partnership with Lin BioScience, we’ll be starting a first-in-human Phase 1 trial this year. We’re starting with patients with relapsed or refractory acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia in blast crisis and resistant to oral tyrosine kinase inhibitors, and myelodysplastic syndrome that has failed prior therapy.
This compound also has broad activity in solid tumors, and we’ve shown in the lab that it’s effective against triple negative breast cancer, as well as thyroid cancer, ovarian cancer, pancreatic cancer, lung cancer, and melanoma among others. What’s interesting is that these cancers, as well as some leukemias and lymphomas, tend to be resistant to traditional chemotherapies when they overexpress CDC7. The potential is there to help a wide range of patients, so these next steps are very exciting.