Terry Kenakin: Allostery, Bias, and the Assays That Changed What We Could See

SCIENTIFIC ABSTRACT

Receptor pharmacology spent decades describing a drug as if a single number

could carry it: one potency, one efficacy, one response per receptor. Terry

Kenakin's career tracks what happened when that picture came apart.

Trained first as a chemist in Edmonton and then as a pharmacologist, Kenakin

spent more than thirty years in drug discovery at Burroughs Wellcome and

through the Glaxo iterations. A CCR5 screen for HIV entry returned an

allosteric hit and pushed an entire program into learning allostery the hard

way. This conversation follows the thread from that hit through probe

dependence to biased signaling, and to the argument that neither is new.

Proteins have always moved and always chosen their partners. Pharmacology

simply lacked the assays to notice.

Kenakin is direct about what the field still cannot do, particularly the

distance between a clean bias measurement in cells and a compound that behaves

predictably in a person. He also describes flying back to London to show James

Black the lab he had built, and being asked a single question about kinetics

that reset everything he thought he had finished learning.

ABOUT TERRY

Terry Kenakin is a professor in the Department of Pharmacology at the

University of North Carolina School of Medicine in Chapel Hill. He works on

receptor pharmacology, allosteric protein function, and drug discovery, with a

long focus on how drug activity should be quantified so that the numbers travel

between systems rather than describing only the cells they came from.

Before UNC he spent seven years at Burroughs Wellcome and twenty five years

across Glaxo Inc, GlaxoWellcome, and GlaxoSmithKline, where he led a CCR5 entry

inhibitor program for HIV and worked on chemokine receptors, MC4R, and GLP1. He

continues to consult with industry on allosteric programs. He is also the author

of A Pharmacology Primer, now in preparation for its sixth edition, a book he

describes writing largely to teach himself the field as it kept changing.

SCIENTIFIC THEMES OF THE CONVERSATION

- Allostery and probe dependence as ordinary protein behavior rather than

special cases

- Biased signaling, and why it looked rare only while the assays were blind

to it

- Chemokine receptor redundancy reconsidered as fine tuning

- Targeting a single protein versus screening the whole phenotype

- Translation: why bias is easy to measure and hard to carry into a body

- Building a scientific career across industry and academia

KEY INSIGHTS FROM THE CONVERSATION

The field did not discover allostery. It acquired the eyes to see it.

Kenakin points out that enzymologists were years ahead of pharmacologists on

allostery, and that the delay was technological rather than conceptual. Screens

were built on binding, so they returned compounds that worked by steric

hindrance. Once functional screening arrived, allosteric hits started appearing

everywhere they had presumably always been.

Bias is what proteins do, not an exception to what proteins do.

A protein has a shape, the shape dictates which partners it engages, and a

ligand that alters the shape alters the interaction. Kenakin frames probe

dependence as the mechanism and biased signaling as the name pharmacology

later gave it. He now expects a screen to return compounds that signal

differently from the natural hormone, rather than treating such a compound as

a curiosity.

An allosteric hit dragged one HIV program into years of hard schooling.

The CCR5 program at Glaxo found an allosteric compound in the early nineties,

and Kenakin describes the two years that followed as the allosteric school of

hard knocks: exhilarating, frustrating, and baffling to the chemists who

depended on consistent answers from the biologists. The compound, aplaviroc,

lowered viral load and reached humans before failing in phase three on liver

toxicity. The program still reshaped how he thinks about protein function.

Redundancy in the chemokine system turned out to be resolution.

Twenty some receptors and roughly fifty chemokines were long read as a fail

safe arrangement. Kenakin points to work from Trudy Kohout in the Lefkowitz lab

showing that CCL19 and CCL21 act differently at CCR7, one recruiting arrestin

and one not. What looked like duplication was nature using bias for fine

tuning.

The aha moments ran in the opposite direction from the phrase.

Reading the Spengler work on PACAP analogs that reversed potency across

pathways, Kenakin found something his training could not accommodate. Seeing

that a drug could carry more than one efficacy, he says, shattered a model he

had felt secure in. He is unusually plain about what this felt like: not the

relief of finally seeing, but the recognition that his world had been too

simple.

Quantifying bias is the easy half. The body is the hard half.

Kenakin describes an entire evening session at a Gordon conference spent on the

translation problem, with no resolution. Two compounds can be cleanly separated

in a simple assay and then meet an in vivo environment that adds nuances nobody

modeled. That gap, he argues, is where drugs fail, and closing it is the work

that actually matters for making better ones.

Fragile nodes, not obvious targets.

Knock out an overexpressed kinase and a tumor may simply route around it.

Kenakin describes systems as collections of nodes, some redundant and some

fragile, and puts the case for phenotypic screening as an attempt to find the

fragile ones. He is careful to say this is not his own expertise, which is

itself part of the point: the question has outgrown the era he was trained in.

SELECTED QUOTES

"Research is a privilege, it isn't a right."

"He said, yes, but do you know anything about kinetics? And I said, no, I

don't. Then you know nothing."

"It isn't an aha, now I see. It's an oh, now I don't see."

"I expect a screen to give you a compound that will in some way be biased

differently from the natural hormone. I expect it, because that's what proteins

do."

EPISODE TIMELINE

Timestamps were generated using AI for readability.

- 00:00 Introduction

- 02:19 Chemistry in Edmonton, and the Scotsman who said make them drugs

- 05:45 Why research is a privilege rather than a reward for good marks

- 08:37 Thinking like a chemist inside the vagaries of biology

- 12:15 Drafted into CCR5, and the allosteric school of hard knocks

- 18:28 Probe dependence, bias, and what proteins were always doing

- 22:09 New assays, new eyes, and a richer array of options than expected

- 24:55 Chemokine redundancy, CCR7, and why GLP1 is the favorite

- 30:10 Dinner with James Black and one question about kinetics

- 34:31 Single targets, fragile nodes, and the tumor that laughs at you

- 51:10 Are GPCRs still good targets, after being declared mined out

- 01:01:36 Advice for early career scientists on industry, ego, and technique

- 01:12:07 The aha moments that took certainty away

- 01:15:13 Work, life, and a limit you have to set yourself

GUEST LINKS

- LinkedIn: https://www.linkedin.com/in/terry-kenakin-6634a43b/

- UNC Department of Pharmacology: https://www.med.unc.edu/pharm/directory/terry-kenakin-phd/

- Amazon: https://www.amazon.com/Terry-Kenakin/e/B01I2QNYWO/

- ResearchGate: https://www.researchgate.net/profile/Terry-Kenakin

- PubMed: https://pubmed.ncbi.nlm.nih.gov/?term=Kenakin+T

- Dr. GPCR Ecosystem: https://www.ecosystem.drgpcr.com/search?q=Terry+Kenakin