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pY705 pS727

N-terminal Coiled-coil DNA-binding Linker SH2 STAT3 TAD NCdomain domain domain domain domain

Protein-protein Regulation of STAT specific, Stabilizes Phosphotyrosine Transcriptional interaction activation DNA-binding DNA-binding binding activity

FERM SH2-like Pseudokinase Kinase (JH1) JAK NCdomain domain (JH2) domain domain

Receptor Receptor Non-catalytic domain, Catalytic activity interaction interaction regulatory function

.,96* .2*&66*46*7*28&8.323+"## &2)(311324638*.27869(896*7#C-..INGDH>C: 6C9H:G>C:E=DHE=DGNA6I>DCG:96C9BJI6I>DCH>I:HAD86I:9>C-" 9DB6>C6G:B6G@:9>CI=:HIGJ8IJG: 'JI6I>DC=DIHEDIH>C-..;DG6B>CD68>9H6C93 6G:7DA9:9 :ADLI=:EGDI:>CHIGJ8IJG:HD; -..6C9$%>HI=:B6>CGDA:D;:68=EGDI:>C9DB6>C7AJ: .IG6CH68I>K6I>DC9DB6>C >H 696EI:9;GDB9:G6J?D:I6A

IL-6R IL-6 gp130

GFR GF I. Cell membrane

JAK JAKII. JAK JAK JAK JAK

III.

V. STAT STAT IV. i. STAT STAT STAT SOCS ii. VI.

CIS

STAT PIAS STAT

STAT iv. VII. SRC STAT PTPs iii. STAT SHPs SIE/GAS DNA

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H9L@O9QK= ? &'/009F<./),' GJAF9;LAN9LAF?EML9LAGFKAFLMEGJ KMHHJ=KKGJK = ? # <= )=D =L 9D 'MHH=JK *MKK=FRO=A? 9F< *MKK=FRO=A? 0G?=L@=J L@=K= 9DL=J9LAGFK D=9< LG ;QLGCAF= AF<=H=F<=FL MF;GFLJGDD=< ?JGOL@ J=KAKL9F;= LG 9HGHLGKAK ?=F=LA; AFKL9:ADALQ9Fleukemia AML related precursor neoplasms Primary myelofibrosis Myelodysplastic Acute leukaemias of syndromes ambiguous lineage Essential thrombocythemia

Polycythemia vera

Acute myeloid lineage Myeloid lineage Myelodysplastic and leukemias myeloproliferative neoplams Hematological malignances

Acute lymphoblastic Lymphoproliferative Lymphoid lineage leukemia (ALL) neoplasms Chronic lymphocytic T-cell ALL leukemia

B-cell ALL Hairy cell leukemia

T-cell prolymphocytic leukemia Hodgkin lymphoma Non-Hodgkin lymphoma

Precursor lymphoid neoplasms

B- and T-cell lymphoblastic T/NK-cell neoplasms leukemias/lymphomas Mature T/NK-cell B-cell neoplasms neoplasms

Cutaneous Extranodal Nodal Leukemic

Primary cutaneus Extranodal NK-/T-cell Peripheral TLC, not Aggressive NK-cell leukemia γδ-T-cell lymphoma (TCL) lymphoma, nasal type otherwhise specified

Transformed mycosis Entheropathy-associated T-cell prolymphocytic Angioimmunoblastic TCL fungoides TCL leukemia

ALK+ Anaplastic large Systemic EBV+ TCL Mycosis fungoides Hepatosplenic TCL cell lymphoma of childhod

Subcutaneous panniculitis- ALK- Anaplastic large Adult T-cell Sézary syndrome like TCL cell lymphoma leukemia/lymphoma

Primary cutaneus CD30+ Monomorphic epiteliotropic Large granular Follicular TCL lymphoproliferative disorders intestinal TCL lymphocytic leukemia*

Aggressive Indolent

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A -72h -0.3h 0h

Pre-culturing HEK293sie Transfection reagent Cell seeding on STAT3(wt) cells on pre-plated siRNAs siRNA-lipid complexes

68.5h 70h 71.5h 71.8h 72h Incubation IL6 (50ng/ml) Plating cell Fluorescence Plating reporter Luciferase at 37°C induction viability reagent readout assay reagent readout

B -72h -0.3h 0h

Pre-culturing HEK293sie Transfection reagent Cell seeding on STAT3(Y640F) cells on pre-plated siRNAs siRNA-lipid complexes

68.5h 70h 71.5h 71.8h 72h Plating cell Fluorescence Plating reporter Luciferase Incubation at 37°C viability reagent readout assay reagent readout

Total assay time 72h

Primary screen: siRNAs in Reporter activity cut-off 2*SD of negative control pools of 3 tageting 1,056 genes. (activating knockdowns ≥140%, inhibiting ≤40%)

Secondary screen: 182 targeted genes. Reporter activity: at least 2 out of 3 siRNA knockdowns have 546 individual siRNAs (3 per gene). to either inhibit or activate (cut-off: 2*SD of negative control) Validation screen: 25 targeted Reporter activity: at least 2 out of 3 siRNA knockdowns have genes. 75 individual siRNAs to either inhibit or activate (cut-off 2*SD of negative control) (3 per gene). and the response have to match with secondary screen Hit gene selection: 6 kinases 1 phosphatase

Validation for four kinases with kinase inhibitors.

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EAF9FL=J=9;@LJ9FK>=JKL=H HD9L=KO=J= K=9D=<9F<;=FLJA>M?=<9LJ;>EAF9FADAF?/QKL=ECAL9KK9QKO=J=

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AF;M:9LAGF9LX 9F< +AF9@MEA A=M?=< 9Ld?>GJEAF /MH=JF9L9FLO9KJ=EGN=<9F<;=DDKO=J=KMKH=F<=GDDGOAF?9FLA:GJGE AGK;A=F;=K "%0 ;DGF=)i,

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CDCell toxicity Cell viability A Cell toxicity Cabazitaxel, microtubule i. Cabazitaxel, microtubule i. 120 120 50 100 100 80 80 60 60 40 40 % toxicity 40 20 % viability 20 0 0 1 1 10 10 30 0.1 100 0.1 100 [nM] 1000 [nM] 1000 GSK-461364, PLK1 i. GSK-461364, PLK1 i. 20

DSS STAT3(wt) CTX DSS STAT3(wt) 120 120 100 100 80 80 10 60 60 40 40 % toxicity 20 % viability 20 0 0 0 1 1 0 1020304050 10 10 100 100 DSS STAT3(Y640F) CTX 1000 1000 [nM] 10000 [nM] 10000 B Cell viability Filanesib, kinesin i. Filanesib, kinesin i. 100 100 50 80 80 60 60 40 40

40 % toxicity 20 % viability 20 0 0

1 1 10 10 0.1 100 0.1 100 30 [nM] 1000 [nM] 1000

Dinaciclib, CDK i. Dinaciclib, CDK i. 20 120 120

DSS STAT3(wt) CTG DSS STAT3(wt) 100 100 80 80 10 60 60 40 40

% toxicity 20 % viability 20 0 0 0 1 1 0 1020304050 10 10 DSS STAT3(Y640F) CTG 0.1 100 0.1 100 [nM] 1000 [nM] 1000

Microtubule targeting / Selinexor, XPO1 i. Selinexor, XPO1 i. kinesin inhibitor 120 120 100 100 PLK1 inhibitor 80 80 CDK inhibitor 60 60 40 40 % toxicity HSP90 inhibitor 20 % viability 20 0 0 IAP/SMAC mimetic 1 1 10 10 100 100 1000 1000 XPO1 inhibitor [nM] 10000 [nM] 10000

HEK293sie STAT3(wt) HEK293sie STAT3(Y640F) .,96* "## &(8.:&8.324638*(87(*007+631(=8383<.(6*74327*7DCHI>IJI>K:AN68I>K:BJI6CI -..3 EGDI:8IH8:AAH;GDB8NIDIDM>8:;;:8IHD;H:K:G6A9GJ<8A6HH:H>C6:AA.DM!G::C.2 8NIDIDM>8>ING:69DJIL=:C8DBE6G:9ID-..LI :MEG:HH>C<8:AAH #C8:AAK>67>A>ING:69DJI:AA.>I:G !AD .!8=:BDEGDI:8I>DC>HCDI9:I:8I67A: DH: G:HEDCH:8JGK:HD;E:G8:CIIDM>8>IN6C9K>67>A>IN D;" %H>:-..3 DG-..LI8:AAH 77G:K>6I>DCH-- 9GJI>K>INH8DG:> >C=>7>IDG *&% EDAD A>@: @>C6H: % 8N8A>C 9:E:C9:CI @>C6H: "-* =:6I H=D8@ EGDI:>C #* -' >C=>7>IDGD;6EDEIDH>HEGDI:>C -'B>B:I>8H2*) :MEDGI>C 96EI:9;GDBI=:HIJ9N#

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

L=JEAF9D /J;CAF9K=" GFL@=GL@=J@9F< ;9MK=<9FAF;J=9K=G>J=HGJL=J9;LANALQAF /005" :ML FGL AF L@= %( AF;GFKLALMLAN=DQ9;LAN9L=< /00KA?F9DAF? /AF;=L@=C=Q>MF;LAGFG> /'AKLGAF9;LAN9L=/"'K L@AK9DKG AF/005" *=PL O=<=L=JEAF=L@=K=N=F@AL?=F=K O=J= K=D=;LAN=DQ J=?MD9LAF? /00 KA?F9DAF? 3= ?=F=J9L=< $!' ;=DDK LJ9FKA=FLDQ=PHJ=KKAF?9DM;A>=J9K=J=HGJL=J>GJ/00 =JGFl%"* l 9;LAN9LAGFKAL=J=KHGFK==D=E=FL#/ .! +FDQL@=CFG;C AF@A:AL=<:GL@/009F<%"* lAF L@= ?=F= CFG;CA;9FL =>>=;L GF /00 LJ9FK;JAHLAGF9D9;LANALQ GJL@=J=KMDLKO=J=FGF ;GF;DMKAN="A?MJ=

Correlation of reporter activities of STAT3(wt) A and STAT3(Y640F) in primary screen 300

Negative controls Positive controls, siSTAT3

200 Assay controls, siDEATH Screened genes Genes selected for the 2nd screen 2nd screen confirming hits 100 % activity of cells STAT3(Y640F)

0 100 200 300 % activity of cells STAT3(wt)

trascriptional B activity (%) 140

CDC7_1 CDC7_2 CDC7_5 CDK8_1 CDK8_4 CDK8_5 CSNK2A1_10 CSNK2A1_3 CSNK2A1_6 DDR2_1 DDR2_2 DDR2_3 PI4KII_1 PI4KII_2 PI4KII_6 PTPRH_1 PTPRH_2 PTPRH_5 CSK_1 CSK_2 CSK_3 100 HEK293_SIE_ STAT3(Y640F) 20 HEK293_SIE_ STAT3(wt) + IL-6 missing HEK293_GAS + value IFN-γ (STAT1)

.,96* 7.! 7(6**2 83 .)*28.+= /.2&7*7 &2) 4-374-&8&7* 6*,90&8.2, -=4*6&(8.:* "## !:C:G6A9>HIG>7JI>DCD;EG>B6GNH8G::CL>I=;DAADL JE=>IH=><=A><=I:9 06A>96I:9=>IHL=DH:@CD8@9DLC G:HJAI:9>C68=6C<:D;IG6CH8G>EI>DC6A68I>K>IND;.G6CH8G>EI>DC6A68I>K>IND;K6A>96I:9H>,(=>IH>C " %5-# 5-..3 #& >C9J8:9" %5-# 5-..LI6C9>C# ( γ>C9J8:9" %8:AAH :MEG:HH>C< -..-.. !- G:EDGI:G -..LI 6C9 -..3 ':6C D; I=G:: I:8=C>86A G:EA>86I:H;GDBDC:G:EG:H:CI6I>K::ME:G>B:CI !-':6CD;I=G::>C9:E:C9:CI:ME:G>B:CIHL>I=:68= =6K>C86AG:EA>86I:H )CAN @CD8@9DLC>C=>7>I:97DI=-# -..-..6C9!- -..-..IG6CH8G>EI>DC6A68I>K>IN 6I6>HCDGB6A>O:9IDEDH>I>K:8DCIGDAH>-.. 6C9C:<6I>K: 8DCIGDACDC I6G<:I>C,( 96EI:9;GDBI=:HIJ9N#

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

"! 9F< ;9MK=< AF@A:ALAGF G> LJ9FK;JAHLAGF9D 9;LANALQ AF /005" =PHJ=KKAF?;=DDK :ML>JGEL@=K=LOG/"'K GFDQ"!O9K@A?@DQ=PHJ=KK= /J;KLMGJ= /"'AF@A:ALAGF;GMD/005" HEK293_SIE_STAT3(Y640F) HEK293_SIE_STAT3(wt) + IL-6

A 150 JAK1/2 inhibitor F 150 JAK1/2 inhibitor 125 125 4 h, viability 100 100 8 h, viability 75 75 24 h, viability 50 50 % response % response 72 h, viability 25 25 0 0 1 10 100 1000 10000 1 10 100 1000 10000 ruxolitinib (nM) ruxolitinib (nM) 4 h, activity 8 h, activity CSNK2 inhibitor CSNK2 inhibitor B 150 G 150 24 h, activity 125 125 72 h, activity 100 100 75 75 50 50 % response % response 25 25 0 0 1 10 100 1000 10000 1 10 100 1000 10000 silmitasertib (nM) silmitasertib (nM)

C 150 CDK8 inhibitor H 150 CDK8 inhibitor 125 125 100 100 75 75 50 50 % response % response 25 25 0 0 1 10 100 1000 10000 1 10 100 1000 10000 senexin B (nM) senexin B (nM)

D 150 CDC7 inhibitor I 150 CDC7 inhibitor 125 125 100 100 75 75 50 50 % response % response 25 25 0 0 1 10 100 1000 10000 1 10 100 1000 10000 BMS863233 (nM) BMS863233 (nM) EJ150 DDR2 inhibitor 150 DDR2 inhibitor 125 125 100 100 75 75 50 50 % response % response 25 25 0 0 1 10 100 1000 10000 1 10 100 100010000 regorafenib (nM) regorafenib (nM) .,96*+-+2*324'-+

.,96*37*&2)8.1*)*4*2)*2(=83;&6)771&00130*(90*.2-.'.83678&6,*8.2,8-*/.2&7* -.87 +631 7.! 7(6**27 .2 "## % 0*+8 (30912 &2) .2)9(*) "## ;8 6.,-8 (30912*<46*77.2,(*007':6C6C9:GGDG76GH;GDB6IA:6HIILD>C9:E:C9:CI:ME:G>B:CIHL>I=ILD I:8=C>86AG:EA>86I:H 96EI:9;GDBHIJ9N# /-85+324'-+ + **+-*$"3*$(,'(!(2-012 0&$2(,& .'-1.'-07* 2(-, 0G:=LL=JMF<=JKL9F9;LAGFG>L@=K=D=;L=>=;LG>L@=/00 59FL=J;GEHGMFGJL@=9KK9Q K@A?@9Kn)JMPGDALAFA: L=JGJ@"A?MJ= :ML@9<9KLJGF?AF@A:ALGJQ=>>=;LGF%( AF>=;L/00/H@GKH@GJQD9LAGFAF=AL@=JG>L@=;=DDEG<=DK /=F=PAF J=?GJ9>=FA:9F<)/;9MK=H5AF/005" ;=DDK :MLFGF=G>L@=K=;GEHD=L=DQ9:GDAK@=>=;L AF %( AFL=J @ H=JLMJ:9LAGFK:ML>=;LAF%( AF H59F>=;L=< L@=D=N=DKG>LGL9D/00HJGL=AFAF:GL@/00OL 9F

A HEK293_SIE_STAT3(Y640F) cells E HEK293_SIE_STAT3(wt) cells + 50ng/ml IL-6

DMSOruxolitinibsenexinsenexin Asilmitasertib BregorafenibBMS863233 DMSOruxolitinibsenexinsenexin Asilmitasertib BregorafenibBMS863233 pY705-STAT3 pY705-STAT3 total-STAT3 total-STAT3 alpha-tubulin alpha-tubulin pS727-STAT3 pS727-STAT3 total-STAT3 total-STAT3 alpha-tubulin alpha-tubulin

B pY705-STAT3 to tot-STAT3 F pY705-STAT3 to tot-STAT3 2.0 p = 0.004 2.0 p < 0.001 p = 0.0064 1.5 1.5 p < 0.001 p = 0.0014 1.0 1.0

0.5 0.5

Fold change to DMSO 0.0 Fold change to DMSO 0.0

ruxo silmi ruxo silmi snx Asnx B rego snx Asnx B rego DMSO BMS86 DMSO BMS86 C pS727-STAT3 to tot-STAT3 G pS727-STAT3 to tot-STAT3 p < 0.001 2.0 p = 0.0441 2.0 p = 0.0314 1.5 p = 0.0123 1.5

1.0 1.0

0.5 0.5 Fold change to DMSO Fold change to DMSO 0.0 0.0

ruxo silmi ruxo silmi snx Asnx B rego snx Asnx B rego DMSO BMS86 DMSO BMS86 D total-STAT3 to alpha-tubulin I total-STAT3 to alpha-tubulin p = 0.0192 2.0 p = 0.0014 2.0 p = 0.0160 p < 0.001 1.5 1.5 p = 0.0128

1.0 1.0

0.5 0.5 Fold change to DMSO Fold change to DMSO 0.0 0.0

ruxo silmirego ruxo silmi snx Asnx B snx Asnx B rego DMSO BMS86 DMSO BMS86

.,96*#-**++*(83+8-*-.8/.2&7*.2-.'.8.3232"## 4-374-36=0&8.32.2"## % &2) .2)9(*)"## ;8*<46*77.2, 7.*(*007" %H>:-..3 8:AAH #& >C9J8:9" @H>:-..LI8:AAH 96EI:9;GDBI=:HIJ9N#

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

A Cell viability: STAT3 vs TP53 mutant B Cell toxicity: STAT3 vs TP53 mutant 4 2.0 AMG-232 dexamethasone idasanutlin momelotinib 3 1.5 mepacrine ruxolitinib midostaurin omacetaxine volasertib etoposide tosedostat A-1331852 2 momelotinib 1.0 gemcitabine

ruxolitinib palbociclib -log(P value) -log(P value) filanesib filanesib navitoclax 1 0.5 birinapant cytarabine A-1331852 navitoclax 0 0.0 -15 -10 -5 0 5 10 15 20 -10 -5 0 5 10 15 Difference in DSS Difference in DSS

Mean DSS values C ruxolitinib D ruxolitinib 120 100 Selective towards STAT3 mut 100 80 Selective towards TP53 mut 80 60 60 40 40 % toxicity % viability 20 20 0 0 1 10 100 100010000 1 10 100 100010000 [nM] [nM] Cell lines E navitoclax F navitoclax 120 100 YT 100 80 NK-YS STAT3 mut 80 60 SNK-6 60 40 NK-92 40 % toxicity % viability 20 NKL 20 TP53 mut 0 0 IMC-1 1 10 100 100010000 1 10 100 100010000 KHYG-1 [nM] [nM]

G idasanutlin H idasanutlin 120 100 100 80 80 60 60 40 40 20 % toxicity % viability 20 0 0 -20 1 10 100 100010000 1 10 100100010000 [nM] [nM]

.,96* 69, 7*27.8.:.8.*7 3+ 36 198&28 1&0.,2&28 (*007 ':6C 9GJ< H:CH>I>K>IN H8DG:H -- 68GDHH (% 8:AA A>C:H >C K>67>A>IN 6C9IDM>8>IN G:69DJI DH: G:HEDCH:H D; G:EG:H:CI6I>K:9GJ

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

A Synergies in viability readout B 20 TP53mut Venetoclax STAT3mut Navitoclax 15 Cytarabine Alisertib 10 Etoposide Methotrexate 5 Idarubicin Volasertib synergy score ZIP 0 Paclitaxel Vincristine -5 AMG-232 Idasanutlin S63845 Tipifarnib S63845 NavitoclaxVenetoclaxIdasanutlinSiremadlin Lonafarnib Topotecan Dexameth.Methylpred. Methylprednisolone Dexamethasone Napabucasin Synergies in toxicity readout AZD1152-HQPA C 20 Tipifarnib TP53mut Copanlisib 15 STAT3mut Taselisib 10

NK-92 NKL IMC-1 KHYG-1 SNK-6 YT NK-YS Duvelisib 5 0

ZIP synergy score ZIP -5 TP53 STAT3 -10 - 10 0 < 10 Missing value S63845 Navitoclax SiremadlinTipifarnib Viability Dexameth.Methylpred. VenetoclaxIdasanutlin Lonafarnib d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

y perturbation 3-day perturbation, 6-day recovery B 140 140 120 120 100 100 80 80 60 60 % viability % viability 40 40 20 20 0 0 DMSO Ruxo. Dexa. Dexa. Mepr. Mepr. DMSO Ruxo. Dexa. Dexa. Mepr. Mepr. 100nM 200nM +ruxo. 200nM +ruxo. 100nM 200nM +ruxo. 200nM +ruxo. C D 140 140 120 120 100 100 80 80 60 60 % viability % viability 40 40 20 20 0 0 DMSO Ruxo. Idas. Idas. Sire. Sire. DMSO Ruxo. Idas. Idas. Sire. Sire. 100nM 300nM +ruxo 300nM +ruxo. 100nM 300nM +ruxo 300nM +ruxo. E F 140 140 120 120 100 100 80 80 60 60 % viability % viability 40 40 20 20 0 0 DMSO Ruxo. Tipi. Tipi. Lona. Lona. DMSO Ruxo. Tipi. Tipi. Lona. Lona. 100nM 200nM +ruxo. 300nM +ruxo. 100nM 200nM +ruxo. 300nM +ruxo.

YT NK-92 NK-YS NKL SNK-6 IMC-1 .,96* <8*2)*) )69, 4*6896'&8.32 &77&=7 ->CI>C>7 8DB7>C6I>DC :;;:8I DC K>67>A>INL>I=8D>9H''>C=>7>IDGH6C9;6GC:HNAIG6CH;:G6H:>C=>7>IDGH 6I6;GDB ILD >C9>K>9J6A :ME:G>B:CIH 9DC: >C 6I A:6HI IG>EA>86I:H 77G:K>6I>DCH ,JMD GJMDA>I>C>7 9:M6 9:M6B:I=6HDC: B:EG B:I=NAEG:9C>HDADC: >96H >96H6CJIA>C H>G: H>G:B69A>C I>E> I>E>;6GC>7 ADC6 ADC6;6GC>7

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

DrugsDrugs present Drugs removed Drugs present Drugs removed A B YT NK-92 40 40

30 30

20 20

10 10 Cell count (million cells) Cell count (million cells) 0 0 0 102030405060 0 102030405060 DAY DAY C D NK-YS NKL 40 40

30 30

20 20

10 10

Cell count (million cells) 0 Cell count (million cells) 0 0 102030405060 0 102030405060 DAY DAY EF SNK-6 IMC-1 40 40

30 30

20 20

10 10 Cell count (million cells) 0 Cell count (million cells) 0 0 102030405060 0 102030405060 DAY DAY

DMSO dexametasone, 200nM dexametasone+ruxolitinib ruxolitinib, 100nM tipifarnib, 200nM tipifarnib+ruxolitinib idasanutlin, 300nM idasanutlin+ruxolitinib

.,96* 32,)69,86*&81*28.)*28.+.*74*67.78.2,6*74327*7.2+.:*(*000.2*7&DCC"## BJI6CI8:AAH6C9# BJI6CI8:AAH 6I6;GDBH>CB:CI

,#% +(*7(,'(!(2(-,1'-514 0($# 0$1.-,1$1(,!$25$$,2'$"$***(,$1 .MPGDALAFA:;GE:AF=9EADQAF@A:ALGJKK@GO=>=;LAF# EML9FL;=DDKAF:GL@G>L@= =PL=F<=< 9KK9QK 2=F=LG;D9P 9?9AF O9KFbL 9K =>>=;LAN= *GL9:DQ L@= /00 5 EML9FL/*' ;=DDDAF=L@9LO9K?=F=J9DDQK=FKALAN=LGK=N=J9D LJ=9LE=FLK K@GO=N9,6)/ G:K=JN=>=;LAN= L@9FGL@=J ( >9EADQ AF@A:ALGJK 9FGJ= O=K=D=;L=< LG>GDDGO MHL@= / AF 00, 9KK9Q "A?MJ= $ %F L@= 00, 9KK9QK F) / ;GE:AF=KAP;=DDDAF=K "A?MJ= # $ AF=9KA:D=9HHJG9;@>GJLJ=9LAF?L@=E9DA?F9FL*' ;=DDK '-022$0+#03&0$1.-,1$1 0$.--0.0$#("2-01-% *-,&2$0+#03&0$1.-,1$1 *=PL O=9KC=<@GOO=DDL@=DGF? L=JEJ=KHGFK=KG>L@=KAF?=DGF? L=JE;GEHD=L=J=KHGFK=K 0@==FL@==PL=F<=< <9Q9F< <9Q9KK9QKO=J=:=LL=JAF=FJA;@AF?>GJ DGF? L=JE ;GEHD=L= J=KHGFK=K :ML OGMD< K=D=;L >GJ KGE= >9DK= HGKALAN=K /LJACAF?DQ L@=K@GJL L=JEKQF=J?QK;GJ=KO=J=FGL;GJJ=D9LAF?OAL@L@=DGF? L=JE J=KHGFK=K "A?MJ= 0@=J=>GJ= L@= K@GJL L=JE // N9DM=K 9F< KQF=J?Q K;GJ=K>GJNA9:ADALQ9F>=;LAN=DQ9F

9-day perturbation 3-day perturbation, 6-day recovery A B

140 140

120 120

100 100

80 80

60 60

% viability 40 % viability 40

20 20

0 0 DMSO ruxo. S638. S-638 Navi. Navi. Vene. Vene DMSO ruxo. S638. S-638 Navi. Navi. Vene. Vene 100nM 300nM +ruxo 300nM+ruxo. 300nM +ruxo. 100nM 300nM +ruxo 300nM+ruxo. 300nM +ruxo.

Drugs present Drugs removed Drugs present Drugs removed Drugs present Drugs removed CDYT (STAT3mut) NK-YS (STAT3mut) ESNK-6 (STAT3mut) 4 4 4

3 3 3

2 2 2 10^7 cells 10^7 cells 10^7 cells

STAT3 mutant 1 1 1

0 0 0 0 102030405060 030506010 20 40 0 102030405060 DAY DAY DAY F NK-92 (TP53mut) NKL (TP53mut) IMC-1 (TP53mut) 4 GH4 4 DMSO ruxolitinib, 100nM 3 3 3 S63845, 300nM S63845+ruxolitinib 2 2 2 10^7 cells 10^7 cells 10^7 cells

TP53 mutant 1 1 1

0 0 0 0 102030405060 0 102030405060 0 102030405060 DAY DAY DAY .,96* &2) +&1.0=.2-.'.8367.2*<8*2)*)&2)032,8*61&77&=7 96N6HH6N 96N 6HH6N E:G :68= 8:AA A>C: &DC< I:GB I>B: ID EGDDC 6HH6N L>I= '& >C=>7>IDG - 8DB7>C:9L>I=GJMDA>I>C>7>C"## BJI6CI# BJI6CI(% 8:AAA>C:H 77G:K>6I>DCH,JMD GJMDA>I>C>7- -(6K> C6K>ID8A6M0:C: K:C:ID8A6M

ABTTP vs DSS (viability) TTP vs DSS (toxicity) Complete Complete response response 60 60

40 40

20 20 Day of cell duplication, TTP Day of cell duplication, TTP 0 0 0 10203040 0 10203040 DSS value in viability readout DSS value in toxicity readout

CDTTP vs %-inhibition (3+6-day assay) TTP vs %-inhibition (9-day assay) Complete Complete response response 60 60

40 40

20 20 Day of cell duplication, TTP Day of cell duplication, TTP 0 0 -20-20 0 20 40 60 80 100 -20 0 20 40 60 80 100 %-inhibition %-inhibition

Cells/treatments Overlapping range

Responding cells/treatments Responding range Non-responding cells/treatments Non-responding range .,96* 6*).(8&'.0.8= 3+ ).++*6*28 &77&= 6*&)3987 83 8-* (*00 6*(3:*6= )&= .2 8.1*83 463,6*77.32 ## DBE6G>HDC D; I=: 96N D; G:8DK:GN >C ..* 6HH6N ID 96N 6HH6N -- G:69DJIH6C9:MI:C9:9 96N6HH6NH 6H:9DCI=:8DGG:A6I>DCD;9>;;:G:CI6HH6NG:69DJIHIDI=: 96ND;I=:8:AAG:8DK:GN>C..*6HH6NG:K:6A:9I=6II=::MI:C9:96HH6NH6G:7:II:G>CEG:9>8I>CC6I>DCH/29/753 96EI:9;GDBI=:HIJ9N##

,.* ) ),,"*,+,+1!)# .!#))/ .#+,0 -.#",*'+ +0)5 $$#!0#" 5(#5".1% !,* '+ 0',+/ 0GAFN=KLA?9L=L@==>>=;LG>9KAF?D=>=;L=<:Q9DDL=KL=<;GE:AF9LAGFKJ=KMDLAF?AF;=DDDGKK 9F>=;L=<:QJMPGDALAFA:GJL@= L=KL=<L@=,) AKGD9L=KAFL@=;GE:AF9LAGFK;9MK=<9KKLJGF?;QLGKL9LA;GJ ;QLGLGPA;J=KHGFK=K>GJL@=,) K9K>GJL@=E9DA?F9FL*' ;=DDDAF=KKLM

Dexamethasone Tipifarnib Idasanutlin S-63845 A

100 100 100 100 75 75 75 75 50 50 50 50 25 25 25 25 % to DMSO CD56+ NK-cells 0 1 10 100 1000 1 10 100 1000 10000 1 10 100 1000 10000 0 1 10 100 1000 Drug [nM] Drug [nM] Drug [nM] Drug [nM] B

100 100 100 100 75 75 75 75 50 50 50 50 25 25

% to DMSO 25 25

CD45+ leukocytes 0 1 10 100 1000 1 10 100 1000 10000 1 10 100 1000 10000 0 1 10 100 1000 Drug [nM] Drug [nM] Drug [nM] Drug [nM] C

100 100 100 100 75 75 75 75 50 50 50 50 25 25 % to DMSO 25 25 CD3+ T-cells

0 1 10 100 1000 1 10 100 1000 10000 1 10 100 1000 10000 0 1 10 100 1000 Drug [nM] Drug [nM] Drug [nM] Drug [nM] D

100 100 100 100 75 75 75 75 50 50 50 50 25 25 25 25 % to DMSO CD19+ B-cells 0 1 10 100 1000 1 10 100 1000 10000 1 10 100 1000 10000 0 1 10 100 1000 Drug [nM] Drug [nM] Drug [nM] Drug [nM]

Dexamethasone Tipifarnib Idasanutlin S-63845 Dex. + 100nM ruxo Tipi. + 100nM ruxo Ida. + 100nM ruxo S-63. + 100nM ruxo Dex. + 300nM ruxo Tipi. + 300nM ruxo Ida. + 300nM ruxo S-63. + 300nM ruxo ruxolitinib ruxolitinib ruxolitinib ruxolitinib

.,96* ++*(83+834)69,(31'.2&8.32732-*&08-= 7&+8*6 )&=)69,86*&81*28 ;;:8ID; GJMDA>I>C>7I:6A H>CC6I>DCHL>I= C'GJMDA>I>C>7DG6C<:DG C'GJMDA>I>C>7 G:9DC(% 8:AAH A:J8D8NI:H . 8:AAH6C9 8:AAH ':6C6C9 HI6C96G99:K>6I>DCHD;ILD*'H6BEA:H9DC:6IA:6HI>C9JEA>86I:H 4-#.'*#+0 )-.,$')'+%,$-.#"'!0#"".1% ('+ /# $$'+'0'#/ %F L@AK KLM>AFALA=K "JGE L@=K= HJ=>AFALA=K O=J= =PH=JAE=FL9DDQN9DA<9L=>AFALA=K:=LO==F

ALAFA: H9RGH9FA: 9F< F=>D9E9HAEG< 9F< CAF9K=K ( 4( .' 0' !#". "' "5* $!. $!. %#". %FK. %0' &' 2!#". ( ' (5* ,5' /J; /5'9F<0.' 9LnD 9KK9Q NGDME= AF O=DD 9KK9Q HD9L=K 0@= AFL=J9;LAGFK L@9L O=J= FGL E=9KMJ=GJ2!#".AF@A:ALGJ;=ALAFA:.' "A?MJ= 0@=H),'fAF@A:ALGJF=>D9E9HAEG<> L9J?=LAFL=J9;LAGFK>GJ2!#".AF@A:ALGJ LANGR9FA: 9K=< GF HJ=> L9J?=LK > L9J?=LAFL=J9;LAGFKO=J=>GDDGO=A=< >GMJ FGN=D LANGR9FA: G>> L9J?=LK

".' ( /('9F<"5* "A?MJ= L@9LK@GO=

% n) 9F9DK=HGKALAN=K

A 9 KDR, Cediranib

8 B Tivozanib off-targets EGFR, Lapatinib FRK 120 7 EGFR, Gefitinib ABL1 BRK, 100 Pazopanib SLK 80 FYN A Predicted pKi [M] 6 LYN B, Pazopanib 60 VEGFR2, Gefitinib

% inhibition 40 VEGFR2, Lapatinib 5 20 0 56789 0.1 1 10 100 1000 10000

Measured pIC50 [M] Tivozanib, [nM] Predicted pKi [M], (blinded) Predicted pKi [M], (not measured in Metz et al. 2011) Predicted pKi [M] .,96* +-+2*324'-+ 

.,96* 314&6.7323+(31498&8.32&00=46*).(8*)&2)*<4*6.1*28&00=1*&796*):&09*7

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