Taking high-throughput screening and making it better
CEO: Norbert Bischofberger
Based: Cambridge, Massachusetts
Founded: June 2017
Clinical focus: Cancer
The scoop: Any company that can attract the interest of longtime Gilead R&D leader Norbert Bischofberger, Ph.D., is going to be worthy of note, but Kronos’ drug discovery platform is particularly remarkable because it could unlock drug targets—such as complex transcription factors—that hitherto have been thought practically 'undruggable.'
What makes Kronos fierce: The startup is trying to reinvent high-throughput screening—a stalwart of drug discovery for decades—by flipping it on its head.
HTS typically involves isolating a drug target such as a protein and screening compounds against it, but Kronos’ platform—known as small molecule microarray (SMM)—does the reverse, fixing thousands of small-molecule candidates on a surface using printing technology. Crucially, that means that instead of isolated proteins, you can screen whole cell extracts.
“The advantage of this is that proteins often don’t exist in isolation,” said Bischofberger. “Often proteins intracellularly are associated with other proteins. Once you remove them from the cellular environment, often the tertiary structure changes and the protein might not be the same.” SMM sidesteps those problems and could help identify binding compounds that would not be discovered using conventional methods.
“We may not know what other factors a target is associated with, but it doesn’t matter because our screen takes that into consideration—you are almost agnostic to what that target looks like," he said.
Kronos has licensed three lead compounds that came out of screening at the lab of Angela Koehler, Ph.D, of MIT, Kronos’ scientific founder and developer of the SMM platform. They are an androgen receptor antagonist for prostate cancer, a MYC inhibitor and an undisclosed oncology drug, all currently at the pharmaceutical optimization stage.
The androgen receptor program is the most advanced and works differently from current prostate cancer drugs that either block androgen hormones at ligand receptors or inhibit their synthesis. While these can be effective, they often do not stop the cancer returning, a lot of times because resistance develops at the ligand receptor.
There are other binding domains on the receptor, however, and Kronos’ drug works via these domains to bypass that resistance. That means it should be active in patients with resistance mutations such as AR-V7 in whom androgen deprivation therapy doesn’t work—and handily, there’s a commercial test that could be used to select patients with AR-V7 mutations for clinical testing. Around 30% to 40% of patients who have failed current androgen therapy carry that mutation, said Bischofberger, who estimated that Kronos could be in a position to start trials of a lead candidate in 2019.
Meanwhile, Myc (and an associated protein called Max) has been a longstanding target in cancer because the pathway is upregulated in many tumor types. It has, however, resisted efforts to develop effective inhibitors, like many molecules that bind to DNA, because these tend to have complex, multisite binding patterns. To sidestep that issue, Kronos has developed a compound that doesn’t act as a direct Myc inhibitor.
Max and Myc each can pair up into "homodimer" compounds known as Max/Max and Myc/Myc, but also combine into Myc/Max, a "heterodimer" found in excess in cancer. By stabilizing Max/Max, Kronos' drug ties up that protein in homodimers and keeps Myc/Max heterodimers from forming.
It’s a more attractive ‘light-touch’ approach, said Bischofberger, because simply inhibiting Myc may not be a good idea from a safety perspective; it's involved in many cellular processes crucial to cell survival. “With this you do not shut down Myc, you simply shift the equilibrium and diminish [its] concentration,” he noted.
A third string to Kronos’ bow is an SMM-screening program looking for proteolysis-targeting chimeras (PROTACs), an emerging group that includes immunomodulatory imide drugs such as myeloma therapy Revlimid (lenalidomide). PROTACs are double-headed molecules capable of breaking down unwanted proteins inside the cell, and this could become an additional platform technology for Kronos.
“In theory, you could use this approach to degrade any intracellular or membrane protein,” according to Bischofberger, who says this project may be more suitable for a corporate partnership once proof-of-concept data is available, possibly next year.
Kronos has five full-time staff in Cambridge, but employs around 20 workers in India, mainly covering medicinal chemistry and biology, to reduce costs as it works on its lead compounds. The intention is to keep its lead three compounds in-house though clinical concept testing, and it may have to raise additional funds for that effort in the first half of 2019.
Investors: Kite pharma founder Arie Belldegrun (BellCo Capital); Gilead Sciences’ chairman John Martin; Norbert Bischofberger; Omega Funds; Vida Ventures