Bloomberg Businessweek - USA (2019-10-14)

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PHOTO: GEORGE ETHEREDGE/BLOOMBERG; ILLUSTRATION BY

MAR

ÍA MEDEM

genome.”InMay,Amgenspent$167millionto

acquireDanishbiotechcompanyNuevolutionAB

foritsscreeningtechnologythatwillhelpit hunt

forproteindegraders.

Thefirsttargeteddegraderdrugsarejustbegin-

ninghumantrials,soscientistswon’tknowhow

welltheyworkinpeopleforseveralyears,and

potentialsideeffectsremainlargelyunknown.At

leastthreecancertreatmentsbasedondegrader

technologyhavereachedhumantesting,including

twoArvinasdrugs,andmoreareexpectedinthe

nextyearorso.InJune,Germany’sBayerAGsigned

a pactworthmorethan$110millionwithArvinasto

developproteindegradersfortreatingdiseases,as

wellasagriculturalapplicationsincludingweedand

insectcontrol.ThefirstdrugproducedbyKymera,

whichbreaksdowna proteinlinkedtocertainlym-

phomas,couldbeginhumantrialsnextyear.

The humanbody’sdisposalsystembreaks

downold,unwanted,ordamagedproteinsinto

partsthatlatercanberecycledintonewpro-

teins.A groupofenzymesrecognizesunneeded

proteinsandattachesmoleculartagsthatmark

them for destruction. Cylindrical structures

insidecellscalledproteasomesthencomealong

andcuttheunwantedproteinsupintopieces.

Whentheprocessgoeswrong,withkeyproteins

recycledatanexcessiveorinsufficientrate,cer-

taindeadlydiseasescandevelop,suchascystic

fibrosis,cervicalcancer,orkidneycancer.Drugs

thatblocktheproteasomesbehindtherecycling,

includingTakedaPharmaceuticalCo.’sVelcade,are

alreadyavailabletotreatmultiplemyeloma,whose

fast-growingcellscanbeslowedbythebuildupof

wasteproteins.Onlyrecentlydidscientistsshow

thatit wouldbepracticaltomakedrugsthatdothe

opposite—useproteindegraderstospeedupthe

destructionofdisease-causing proteins.

When Crews first started pursuing the concept

inthelate 1990s, hewasworkingonunder-

standingthe mechanismof anexperimental

cancerdrugthatturnedouttoblockthecell’s

garbage disposalsystem.At a conferencein

Blaine,Wash.,hemetRaymondDeshaies,who

wasstudyingthesamesystemattheCalifornia

InstituteofTechnology.Overbeers,theycameup

withtheconceptofdevelopingdrugstoactivate

theprocesstoget ridofunwantedproteins.

Theideawastodevisea Tinkertoy-likemolecule

withoneendthatstickstoa problemprotein.The

otherendwouldattachtooneofthebody’sgar-

bagedisposalenzymes.Thiswouldtagtheprotein

fordestruction.Butscientistsdidn’tknowmuch

abouthowtolatchontotheenzymesthatmarked

proteinsfordestructionwithsmallchemicals.

Crews’scolleagueswereskepticalthattheidea

hadpracticalapplications.Heworkedforyears

toimprovethetechnology.In 2013 hefounded

Arvinas,whichhasofficeslessthana milefrom

hislabatYale.

By that time, others in the industry had

unpackedsomeofthe world’smostpowerful

drugsandfoundthatdegradingproteinsplayed

a roleintheirsuccess.In2010,Japaneseresearch-

ersshowedthatthalidomide—adrugusedtotreat

bothleprosycomplicationsandmultiplemyeloma

cancer—bound to a key protein involved in

degradationandlimbdevelopment,whichhelped

toexplainhowitcausesbirthdefects. Then,

in2014,otherscientistsshowedthatmultiple

myelomadrugRevlimid,a successortothalido-

midethat’sbeena bestsellerforCelgeneCorp.,

inducedthedegradationofproteinsthatmyeloma

cellsapparentlyuseforgrowth.“Thatis whenthe

fieldwentonsteroids,”saysDeshaies,nowsenior

vicepresidentforglobalresearchatAmgen.

Anotherturningpointcamein2015,when

researchersfromseveralteamsworkinginde-

pendently, including Crews’s lab and scientists

from Dana-Farber Cancer Institute in Boston,

showedthatsmallchemicalsthatcouldpoten-

tiallybepackagedintopillscouldconnectknown

cancer-causingproteinstothebody’sdisposalsys-

temforgrindingup.

NovartisAG now has 60 to 100 scientists at

any given time working on degraders, says James

Bradner, who was on the Dana-Farber team and has

been head of Novartis’s research arm since 2016. So

far they’ve been able to degrade more than 50 pro-

teins in the lab, leading to a half-dozen drugs in early

testing. The first of them, for an undisclosed cancer

target, just began human trials, Bradner says.

In New Haven, Arvinas has taken a more con-

servative approach. It’s working first on improving

● Amount Amgen

spent on Nuevolution to

help it develop protein

degraders

$167m

◀ Something brewing at

the Yale lab

◼ TECHNOLOGY Bloomberg Businessweek October 14, 2019