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The Molecular Assassin

Researcher Kevan Shokat ’86 pioneers a new technique for fighting cancer.

The cancer was spreading.

It began years ago, when a single kidney cell reproduced improperly. A tiny section of DNA was copied wrong. Cellular fail-safes failed. The immune system didn’t recognize the cell as a threat and, unchecked, it began reproducing. Dividing and pressing on, its daughter cells advanced and reproduced with the brainless, remorseless urgency of the bucket-wielding mops in Fantasia. The patient tried one treatment after another, without success; the cancer cells continued their relentless reproduction, threatening to destroy organs, crowd out healthy tissues, and leech away vital resources until the patient died.

Owing to medical confidentiality laws, we can’t say who the patient is, or where he or she lives. We can say, though, that the patient's cancer cells are in retreat, for now, thanks to an experimental drug devised by Kevan Shokat ’86. 

“That’s what I’m hooked on now,” he says of the drug trials. “Seeing [our] drug and seeing every patient on the trial, what cancer they had, how long they had other therapies.” Patients who had been on two-month trial after two-month trial with other ineffectual drugs, then changed to his new compound. “Then they’re on [our] drug for 15 months! You know it’s doing something. It’s so exciting!”

A pioneer in the new intellectual discipline of chemical biology, Kevan uses sophisticated techniques (many of which he invented) to unlock the secrets of kinases, complex molecules that help cells live, work, and—crucially—die. Armed with this knowledge, he is producing new medicines that attack cancer and other diseases by disrupting the chemical machinery of deviant or invading cells, while leaving healthy cells unharmed—molecular arrows, if you will, in a war long dominated by carpet bombing.

On a gray San Francisco day, Kevan sits in his corner office above UC San Francisco’s gleaming new Mission Bay biosciences campus. Chair of UCSF’s department of cellular and molecular pharmacology and tenured at UC Berkeley, Shokat is a Howard Hughes investigator, endowed by the late billionaire’s fortune to advance biomedical science. He runs a lab of 16 graduate students and postdoctoral researchers who dash about with focused intensity, some working behind computers, others fiddling with chemical-laden beakers behind fume hoods, as chemists have always done. 

He shows off the open corridors leading to adjacent laboratories with pride that his team is able to wander freely from lab to lab. As a Hughes investigator, his intellectual property belongs to the university, and there’s no obligation or incentive to keep secrets. “That’s a very big line for me,” he says, “We want the students and everybody to be able to talk anytime, anywhere.”

In his field, Kevan is a rock star: a member of the National Academy of Sciences and the American Academy of Arts and Sciences, Eli Lilly Award winner, Sloane Fellow, and Searle Scholar. He’s come a long way from Albany, California, a quiet, orderly suburb just north of Berkeley, where he grew up working in his parents’ print shop, running presses, printers, folders, and binders in high school and on semester breaks from �����ջ�, which he could never have attended without financial aid. 

His work ethic showed up early at �����ջ�. “Evan Rose ’86 or Deborah Kamali ’85 would come around to the library about midnight, one a.m., to try to get me out.” (He and Deborah are now married; their son, Kasra Shokat ’14, is a junior at �����ջ�.)

“A lot of people at �����ջ� learned early on,” he remembers, “that you’ve got to focus on the important things, and not try to do everything. I ended up trying to do it all.”

Kevan did not come to �����ջ� expecting to be a scientist. Though he’d taken biology and chemistry in high school, he wasn’t brimming with confidence in his first classes. “I didn’t know it very well from high school, so it was all new to me,” he recounts. “I remember all the kids from better schools. They were so far ahead. They got bored and I caught up.”

Professor Phyllis Kosen [chemistry 1981–83] really got him sold on the discipline. “She was just like a New Yorker, chain smoking, fascinated with biochemistry. She didn’t take any bullshit. She wanted top chemistry, and that just got me hooked.” Other lasting influences included his o-chem professor Nick Galakatos ’79 [chemistry 1983–84] and thesis adviser Ron McClard [chemistry 1984–].  

Understanding Kevan’s work requires a step back to look at cells and how they’ve been studied. For all the attention DNA has received as the master blueprint of life, it’s not the part of the cell that keeps the lights on. The actual work of a cell—eating glucose, responding to hormonal signals, taking out waste, flexing (if it’s a muscle cell), transmitting signals (if it’s a nerve cell), reproducing, and politely killing itself when its work is done—is carried out in subtle, complex cascades of chemical causation. The guiding agents of chemical action and energy in a cell are special enzymes called kinases. Kinases transfer energy by moving phosphate radicals from molecule to molecule and from kinase to kinase throughout the cell. Breaking a single link in one of these long, delicate chains can stop a cell dead in its tracks.

When Kevan left �����ջ�, chemically manipulating individual kinases in live cells was something that hadn’t been done. Chemists had little insight into the molecular workings of cells, and biologists were not skilled at chemical approaches to the cell. The two disciplines stood apart from each other, separated by methodology and culture. 

“When Kevan started his independent career,” recalls his PhD adviser, Peter Schultz of UC Berkeley, “chemists did mimetic chemistry. They tried to make organic systems that mimicked biological systems. There were very few chemists who would actually dig into the biology itself.” But after earning his PhD in 1991, Kevan did just that, plunging headlong into cell biology with postdoctoral research in immunology at Stanford. 

Breaking away from one intense discipline and picking up an apparently unrelated one was a spectacular intellectual leap. It wasn’t just difficult, though. “It [was] a huge career risk,” Schultz recalls. “When Kevan went to look for positions, people were confused as to what he was... People didn’t understand whether that person should be in the chemistry department or the biology department.”

“It was risky,” Kevan admits, “but that’s the great thing about coming from �����ջ�. You just go after what’s exciting to you, and you don’t worry about the consequences until later.”

In the early 1990s, genetic engineering (directly manipulating DNA) was the most powerful technique in the cell biologist’s toolbox. It was at Stanford that Kevan first suggested that rather than modifying the cell’s genetic structure to manipulate kinases, one could design small molecules that would block kinase signal paths directly. “I told my adviser about it,” he recalls, “and he said, ‘That’s a stupid idea! Why would I do that? I can just knock out the gene and see what happens.’”

His adviser was advocating the conventional wisdom of the then-dominant approach, in which researchers turn off (“knock out”) a gene and hope to create a viable new mutant for study. This technique works well for studying simple, fast-breeding life forms like E.coli bacteria and yeast cells, but can become cumbersome, expensive, and maddeningly inconclusive with complex, slower-breeding organisms like mice. The “knock out" mouse may never be born, it may die too quickly to study, or its cells may simply reroute its internal chemical signals to circumvent the induced genetic defect. Even if the knock out mouse does develop as hoped, the path from a knock out mutant to a new drug is indirect: you can’t cure a patient by tampering with his or her DNA.

Kevan believed passionately that his chemical approach held huge potential. Unfortunately, Schultz’s prediction proved witheringly accurate. When his postdoctoral research was done, Kevan sat in the academic marketplace like damaged goods, while peers with more orthodox interests landed jobs. “That was the hardest time,” he says, “I got no job offers.” Finally, he landed an assistant position at Princeton, which he accepted, uprooting Deborah’s medical practice and taking Kasra, then two years old, in tow to New Jersey. 

In 1997, he and three collaborators published a paper in the Proceedings of the National Academy of Sciences that would become a signature work. Using genetic engineering, the team created a mutant cell line from Rous sarcoma, a well-studied retroviral chicken cancer that served as their experiment’s control group. The mutant expressed a kinase, v-Src (for “virus-sarcoma” and pronounced “vee-sark”) that would serve as their target. Next, they crafted a series of special molecules to probe the phosphate binding site of the v-Src kinase present in their mutated strain. One of the test molecules, [ɣ ³²P]N⁶-(cyclohexyl) ATP, bound strongly to the mutant cell’s v-Src kinase’s phosphate–binding site, blocking it from receiving or transferring chemical energy. No other kinases found in either cell line showed strong affinity for the test molecule. 

While the nominal objective of the paper, advancing the understanding of kinases in Rous sarcoma, was amply satisfied, the dry, scientific language of the article obscured its true significance. In the conclusion, the authors somewhat coyly predicted that if this technique were to work out with other kinases, “it might be possible to systematically begin to dissect the complex proximal signaling cascades controlled by cellular tyrosine kinases.”

Kevan and his colleagues had demonstrated it was possible to craft small molecules to probe the inner workings of living cells, inventing a powerful new technique to study cell biology that also provided a much straighter path from the laboratory to the doctor’s clinic.

“He built really clever tools, multiple tools,” says Schultz, his adviser at Berkeley. “Elegant solutions that really picked an important biological problem and used chemistry and molecular science in a way that nobody had ever thought about doing.”

The techniques Kevan began inventing at Princeton have been widely adopted by academic and commercial researchers alike because drugs that target kinases offer the promise of extreme specificity. Compared to conventional chemotherapeutic drugs, which mow down healthy and cancerous cells alike in a statistically driven war of attrition, kinase inhibitors attack diseased cells only, leaving healthy cells unscathed. 

“Right now,” he says, “this is probably the mainstream approach for cancer. Twenty years ago, nobody thought you could make a drug specific and potent enough to inhibit the kinases.” Pharmaceutical companies large and small are using the techniques he devised to bring kinase inhibitors to market. “Now it’s a race,” he says. “Who can make the most selective, best drug that’s orally stable, gets across your bloodstream, inhibits potently, and can get the money, the clinical trials, and the patients? Right now, there are so many potential drugs out there, there are not enough patients! You couldn’t test all the ideas.”

In 2006, he coauthored a paper that demonstrated that the mTOR (for “mammalian Target Of Rapamycin” kinase), implicated in several types of cancer, could be chemically blocked. In 2007, he cofounded a pharmaceutical company, Intellikine, which licensed and built on this idea. The company’s two marquee compounds, INK128 and INK1117, attack two broad types of cancer by inhibiting kinase signals in the mTOR and PI3K (phosphoinositide 3-kinase) pathways, respectively. These drugs, which have cleared phase I clinical trials (setting safe doses and proving human safety), showed significant results in patients, both blocking cancer growth, and, in the case of INK128, interrupting metastasis, the devastating spread of cancer cells throughout the body. “We had one patient,” says Intellikine’s cofounder Troy Wilson, “with renal cell carcinoma [whose] tumors shrank dramatically after two cycles of our drug. That doesn’t happen spontaneously.”

In December 2011, Japanese firm Takeda Pharmaceuticals snapped up Intellikine for $190 million. If Intellikine’s drugs make it to market, the deal rises to a total of $310 million.

Not bad for two molecules.   

Thirty years after Chemistry 101 and well into his own career, Kevan might be given a pass for mad-genius abrasiveness, but by all accounts he remains a pleasure to work with. “I’ve been in this business for 15 years, started six different companies, with a lot of different people,” Wilson says. “Kevan, for a lot of reasons, stands head and shoulders above all of them. He’s not only one of the most insightful, thoughtful, brilliant people I’ve ever met, but he’s just a genuinely good human being who always does the right thing... I can think of nobody I’d rather have as a scientific founder.”

Amid the excitement of new discoveries, he remains an active teacher, running his lab as a workshop where students dedicate themselves to inquiry with few constraints. “What I like about running the lab is getting to know people, getting to know their strengths, and then helping them direct themselves onto the path that they find most compelling. That, I think is true for �����ջ�. Nobody tells you you can’t do something, or you can’t go in some direction.”

Kevan encourages his students to pursue their ideas, just as he did. “He’s a great scientist,” notes Joe Kliegman ’06, one of his graduate students, “but he’s also a compassionate human. That’s really important.”

The week we went to press, another of Kevan’s papers had been accepted by Nature, describing a new paradigm, attacking multiple kinase receptors simultaneously. No longer content to address single kinases, he’s studying them as a network, touching on information theory to go after the problem. “I think it really is going to be a big paper...” he says, and you can almost hear the wheels turning in his head.

William Abernathy ’88 is a professional wordsmith and unprofessional ukulele player who lives in the Bay Area.

Tags: Alumni, Research, Health/Wellness