Protein Degradation Therapies

PIONEERING TRANSFORMATIVE PROTEIN DEGRADATION THERAPIES

A new class of small-molecule protein degraders harnessing powerful and universal cellular biology

Forward-looking Statements The foregoing presentation contains forward-looking statements. All statements other than statements of historical fact are forward- looking statements, which are often indicated by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to”, “may,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions. These forward- looking statements include, but are not limited to, statements regarding the therapeutic potential of C4 Therapeutics, Inc.’s technology and products. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. Among the factors that could cause actual results to differ materially from those described or projected herein include uncertainties associated generally with research and development, clinical trials and related regulatory reviews and approvals, and that our product candidates that we are developing or may develop may not demonstrate success in clinical trials. Prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. C4 Therapeutics, Inc. undertakes no obligation to update or revise the information contained in this presentation, whether as a result of new information, future events or circumstances or otherwise.

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▪ Very limited benefit of treatments for metastatic synovial Clear Unmet sarcoma or recurrence following surgery – metastatic Need median survival ~18 months ▪ Median age of diagnosis: 34 years old

Defined Patient ▪ ~900 US yearly incidence of synovial sarcoma cases Population ▪ ~10% of all soft tissue sarcoma Wang et al., 2017

Lack of effective treatment strategies for metastatic disease or reoccurrence following surgery

SMARCB1

SS18-SSX

SS18-SSX fusion SMARCB1 eviction BRD9 dependency BRD9 degradation Defining feature that underlies Incorporation of the SS18-SSXX fusion Loss of SMARCB1 results in a synthetic Targeted protein degradation is an synovial sarcoma pathogenesis ejects SMARCB1 from the BAF complex lethal relationship with BRD9 effective therapeutic strategy

SMARCB1

SS18-SSX

SS18-SSX fusion

▪ Non-random chromosomal translocation t(X:18; p11:q11) ▪ Bona fide driver of pathogenesis

▪ SS18

▪ Epigenetic chromatin regulator ▪ Member of the BAF chromatin remodeling complex

▪ SSX

▪ Potent transcriptional repressor via its KRAB Baranov et al., 2020 domain (not included within the fusion)

SS18-SSX fusion is the defining molecular feature of synovial sarcoma

SMARCB1

SS18-SSX

BAF (Brg/Brahma associated factors) or mSWI/SNF complexes

▪ Multi sub-unit (~15 proteins) ATP dependent chromatin remodeling complexes

▪ Compaction and decompaction of DNA in the nucleus

Adapted from Clapier et al., 2017

▪ Enables replication, selective gene expression and repression

cBAF canonical BAF complexes

▪ Three distinct versions with unique sub- unit combinations ▪ SS18 → ncBAF, cBAF ▪ SMARCB1 → cBAF, pBAF ▪ BRD9 → ncBAF

ncBAF Crosstalk pBAF noncanonical Distinct polybromo localization and activity on ▪ Collaborative interplay between the chromatin complexes to regulate chromatin state

Adapted from Michel et al., 2018

SMARCB1

SS18 SS18-SSX SS18-SSX Roberts et al., 2002 Adapted from McBride et al., 2018

SS18-SSX fusion incorporation results in the ejection of SMARCB1, rendering the cBAF complex dysfunctional and driving an oncogenic state Redistribution of BAF complexes, aberrant chromatin structure, loss of SMARCB1 tumor suppressor function

SMARCB1

SS18-SSX

Synovial sarcoma Malignant rhabdoid tumor (MRT) SS18-SSX fusion driven ejection of SMARCB1 Homozygous SMARCB1 deletion

Briens et al., 2018 Wang et al., 2019

Genome-wide loss of function CRISPR screens identify BRD9 as a unique dependency in synovial sarcoma and malignant rhabdoid tumor cell lines

BRD9 ▪ Bromodomain containing protein 9 ▪ Alternate names ▪ Sarcoma antigen NY-SAR-29 St. Pierre & Kadoch., 2017 ▪ Rhabdomyosarcoma antigen MU-RMS-40.8

▪ Small and compact with two annotated domains

▪ Bromodomain: acetyl lysine reader function

▪ DUF3512 domain: mediates incorporation into the BAF complex

▪ BRD9 is selectively incorporated into the ncBAF complex

Theodoulou et al., 2015

Normal cells Synovial sarcoma cells

cBAF ncBAF cBAF ncBAF SS18-SSX fusion

SMARCB1 Crosstalk Crosstalk

Normal Normal **Compromised** **Aberrant**

▪ Normal chromatin structure Anti-tumor▪ SMARCB1 response null viastate eliminating oncogenic ▪ Wild typeNormal transcription cells spared ▪ Aberrant chromatin structure ncBAF▪ Oncogenic activity transcription in BAF perturbed state

Target rationale: synovial sarcoma tumors are uniquely dependent on BRD9 (synthetic lethal)

SMARCB1

SS18-SSX

Michel et al., 2018 © 2020 C4 THERAPEUTICS, INC. Kadoch & Crabtree., 2013 Wang et al., 2019 15 McBride et al., 2018 Briens et al., 2018 Targeted protein degradation of BRD9 is an effective therapeutic strategy

Inhibition Small molecule inhibition of BRD9 is ineffective

▪ Limited to the disruption of acetyl-lysine bromodomain St. Pierre & Kadoch., 2017 reader function alone

Targeted protein degradation results in the complete loss of BRD9

▪ Maximal disruption of the ncBAF complex oncogenic activity

Degradation activity BRD9 ▪ Potent ▪ Selective ▪ Complete ▪ Durable

Complete disruption of oncogenic BRD9/ncBAF activity CFT7503 ▪ Selective in vitro growth inhibitory activity in human synovial sarcoma cell lines ▪ Complete tumor growth inhibition across CDX and PDX CRBN models of synovial sarcoma Enabling pharmacokinetic profile and drug properties ▪ Oral dosing ▪ Dosing frequency flexibility

Note: CFT7503 is the parent compound of CFT8634, C4 Therapeutics’ lead compound for BRD9.

CFT8634 (100 nM, 4hr) in Yamato-SS

100 nM

4HRS 293T 293T cells

BRD9 [2HRS]

BRD4 [24HRS] % degradation [HiBiT] degradation % BRD7 [24HRS]

Dose [nM]

Dose response degradation Degradation across cellular contexts Degradation selectivity Engineered 293T HiBiT cell lines Endogenous degradation across representative cellular contexts Global proteomic profiling

Potent, complete, selective, and durable dose responsive BRD9 degradation

Yamato [SS18-SSX fusion; BAF perturbed] SW982 [BAF wildtype] Single dose long term growth evaluation Single dose long term growth evaluation

100 BRD9i 100 BRD9i DMSO DMSO 104nM 104nM 1000nM 1000nM 316nM 316nM 100nM 100nM 50 32nM 50 32nM 10nM 10nM

0 0

0 10 20 0 4 8

100 CFT-7503 100 CFT-7503 DMSO DMSO 104nM 104nM Confluence Confluence (%) 1000nM 1000nM 316nM 316nM 100nM 100nM 50 32nM 50 32nM 10nM 10nM

0 0

0 10 20 0 4 8 Time (days) Time (days)

Degradation induced selective growth inhibition in BAF perturbed synovial sarcoma cells

Tumor PK Tumor PD Synovial sarcoma CDX (Yamato-SS) BRD9 degradation in synovial sarcoma tumors

BRD9 100000 CFT7503,CFT-1 10mg/kg7503, 10 mg/kg 1.00 VehicleVehicle CFT7503,CFT-1 75mg/kg7503, 75 mg/kg CFT7503,CFT -10mg/kg17503, 1 0 mg/kg

) 10000 CFT7503, 75mg/kg g CFT-17503, 75 mg/kg

/ Vehicle g

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(

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7503

V l

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CFT

F o

100 D

t C

DC100 r

[

N Yamato Tumor (ng/g) Tumor Yamato a 0.25 CFT-17503 Y 10 40 mg/kg

1 0.00 0 4 8 12 16 20 24 28 32 36 4 24 36 200X Time (h) Time (h)

CFT7503 induces deep and durable BRD9 degradation upon oral administration in a xenograft model of synovial sarcoma

Efficacy Tolerability Synovial sarcoma CDX (Yamato-SS) Synovial sarcoma CDX (Yamato-SS)

3000

M VehicleVehicle (PO QD) 20 VehicleVehicle (PO QD)

E S

CFT7503,CFT-1 76mg/kg503, 6 m (POg/k gQD) (PO QD) CFT7503,CFT-1 76mg/kg503, 6 m (POg/kg QD) (PO QD)

) CFT7503,CFT-1 717mg/kg503, 17 m (POg/k gQD) (PO QD) CFT7503, 17mg/kg (PO QD) 3 2500 CFT-17503, 17 mg/kg (PO QD)

m CFT7503, 50mg/kg (PO QD) CFT7503, 50mg/kg (PO QD)

CFT-17503, 50 mg/kg (PO QD) CFT-17503, 50 mg/kg (PO QD)

(

g 10 e

2000 n

h o

1500 g

i 0

y a

1000 d

B -10

% S

- 500

m a

Y 0 -20 0 7 14 21 0 7 14 21 Days of Treatment Days of Treatment CFT7503 demonstrates dose dependent efficacy in synovial sarcoma and is well tolerated

Efficacy Tolerability Synovial sarcoma PDX (SA13412) Synovial sarcoma PDX (SA13412)

1500 Vehicle (PO QD) 20

M Vehicle (PO QD) VehicleVehic (POle ( PQD)O QD) E

S CFT7503,CFT-175 40mg/kg03, 40 mg /(POkg ( PQDO )QD) CFT7503, 40mg/kg (PO QD)

CFT-17503, 40mg/kg (PO QD) +

1250

)

3 m

e 10

(

n e

1000 a

g r

750 i 0

n d

a 500

B M

-10

2 1

4 250

A S 0 -20 0 7 14 21 0 7 14 21 Days of Treatment Days of Treatment

CFT7503 is efficacious in an adult patient derived xenograft (PDX) model of synovial sarcoma

CLEARANCE VOLUME

Concordant cross-species PK profiles enable confident and favorable human dose predictions

Degradation activity BRD9 ▪ Potent ✓ ▪ Selective ▪ Complete ▪ Durable Complete disruption of oncogenic BRD9/ncBAF activity✓ CFT7503 ▪ Selective in vitro growth inhibitory activity in human synovial sarcoma cell lines ▪ Complete tumor growth inhibition across CDX and PDX CRBN models of synovial sarcoma Enabling pharmacokinetic profile and drug properties ▪ Oral dosing ✓ Note: CFT7503 is the parent compound of CFT8634, ▪ Dosing frequency flexibility C4 Therapeutics’ lead compound for BRD9.

Potential for a safe and effective therapeutic agent with applicability across SMARCB1 deleted cancers Synovial sarcoma, malignant rhabdoid tumor, epithelioid sarcoma