Monte Rosa Therapeutics : AACR 2026 – Selective targeting of CCNE1 using molecular glue degraders for the treatment of CCNE1 amplified cancers

Published: 2026-04-21 19:16:05 ET GLUE

Published on 04/21/2026 at 07:16 pm EDT

‌Selective targeting of CCNE1 using molecular glue degraders for the treatment of CCNE1 amplified cancers

Ralph Tiedt, Monte Rosa Therapeutics

AACR Annual Meeting 2026

‌Monte Rosa MGDs: Opportunity for Paradigm-Changing Medicines

Most disease-causing proteins are

2 Like RNAi and CRISPR, Monte Rosa's MGDs have the potential to unlock undruggable target space

but with the advantages of oral small molecules

‌Molecular Glue Degraders (MGDs) Facilitate Targeted Protein Degradation Independent of Druggable Pockets on Target Proteins

Target protein (neosubstrate)

MGD

contacts

CRBN

Ubiquitin chain

Ternary complex formation

Polyubiquitination

Target protein degradation

(proteasome)

‌CCNE1 (Cyclin E1) is a Target for Solid Tumors with Deregulated Cyclin E1

CDT1

MCMs

G0 - S progression

Centrosome duplication

Cyclin E

MCM5

Cyclin E CDK2

Cell cycle progression/proliferation

Cell death and differentiation

Drug resistance

CCNE1 (Cyclin E1) is a well-recognized human oncogene that drives multiple hallmarks of cancer, and has been considered undruggable

Selective degradation of cyclin E1 can target tumors with deregulated cyclin E1 (amplification or overexpression)

First-in-class Cyclin E1 degraders for CCNE1

amplified cancers

o Ovarian (~20% of ~80K patients), endometrial (~10% of ~50K patients), and gastroesophageal cancer (~10% of ~200K patients), breast cancer and others

Source: Clarivate (2026 drug-treated advanced/metastatic patient incident population in G7 countries)

‌MRT-55811 is a Potent and Highly Selective CCNE1-directed MGD

MRT-55811 is highly selective for CCNE1

CCNE1 degradation led to downstream pathway suppression

CCNE1 degradation induced robust cell cycle arrest

Cell Cycle Phase (% Total)

100

MDA-MB-157

DMSO 1 10 100 1000

[MRT-55811], nM

Protein fold-change (log2)

TMT Proteomics, MDA-MB-157 Rb K/O 1μM, 24h

Western blot, MDA-MB-157, 24h

Flow Cytometry, EdU incorporation, 48h

‌MRT-55811 Induced CCNE1-CDK2 Holoenzyme Degradation in CCNE1 Amplified Cell Lines

MRT-55811 induced co-degradation of CCNE1 and CDK2

MRT-55811 induces CCNE1-CDK2

holoenzyme ubiquitination

MRT-55811 induces CCNE1-CDK2

holoenzyme degradation

CCNE1

CDK2

CDK2:K250

CCNE1:K118

CDK2:K291

CRBN

Ubiquitination

Low

HCC1569, 24h treatment HCC1569, 1μM, 30 min treatment

High

‌CCNE1 MGD Exhibited Superior Selectivity for Cancers with High CCNE1

CCNE1

CDK2

S-Phase CDK4/6

CCNE1 CN MRT-55811 PF-07104091

AZD8421

Azenosertib Lunresertib Palbociclib

* * ‡

Copies of

CCNE1

>10

5-10

4-5

-6

-7

-8

1000nM

100nM

10nM

GI50 Value

10000

Drug GI50 (nM)

1000

100

MRT-55811 PF-07104091 AZD8421 Azenosertib Lunresertib Palbociclib

5-day CyQuant viability; ovarian, endometrial, gastric, and breast lineages (n=68)

Rank-ordered by CCNE1 copy number

* Loss of p16 protein

‡ Loss of RB protein

‌MRT-55811 Induced Growth Suppression is RB-dependent

activity of the CDK family

CDK2i exhibit off-target

CCNE1:CDK2 complex inactivates RB

Growth suppression induced by MRT-55811, but not by CDK2i, is RB dependent

WT RB KO

Growth Inhibition, %

100

AZD8421

WT RB KO

Growth Inhibition, %

100

MRT-55811

0.001 0.01 0.1 1 10

[AZD8421], μM

Kinase Inhibition (%)

0.001 0.01 0.1 1 10

[MRT-55811], μM

MDA-MB-157 MDA-MB-157 RB-KO

100

-20

AZD8421 MRT-55811

100

-20

AZD8421 MRT-55811

µM MRT-55811

CCNE1

p-RB

Vinculin

100

CDK2 CDK3

CDK5

CDK1

CDK4 CDK7

CDK9

CDK6

-20

AZD8421 MRT-55811

MDA-MB-157 (CCNE1 amplified breast) CyQuant assay - 5 day; Western blot - 24 hour treatment

Kinase mobility shift assay [Drug] = 1μM

‌MRT-55811 Treatment Resulted in Tumor Regression and Pathway Suppression in a CCNE1 Amplified Gastric Model

MRT-55811 induced tumor regression in CCNE1 amplified gastric model

MRT-55811 induced E2F signature suppression in tumors

MRT-55811 induced deep CCNE1 degradation and pathway suppression

Tumor Volume (mm3)

mean +/- SEM

1000

300

100

Gastric

0 7 14 21

Days of treatment

Log2 Fold change (relative to vehicle)

-2

-4

-6

125

CCNE1 Protein Expression

Rel. to β-Actin

100

CDK2 Protein Expression

Rel. to β-Actin

125

100

CCNE1

Vehicle

MRT-55811

AZD8421

CDK2

125

pRB Protein Expression

Rel. to β-Actin

100

pCDK2 Protein Expression

Rel. to β-Actin

125

100

pRB (S807/811)

Vehicle

MRT-55811

AZD8421

pCDK2 (T160)

MRT-55811

Vehicle

MRT-55811,

100mg/kg QD

AZD8421,

150mg/kg BID

MRT-55811 AZD8421

MRT-55811 AZD8421 0 0

Vehicle

AZD8421

Vehicle

AZD8421

21-day efficacy study in MKN1 CDX

RNASeq

Tumors collected 8h post first (MRT-55811)

or 1h post second (AZD8421) daily dose

Western blot, day 21

Tumors collected 8h post first (MRT-55811)

or 1h post second (AZD8421) daily dose

AZD8421 dosing selected based on 2024 AACR Annual Meeting disclosure

‌MRT-55811 Treatment Resulted in Tumor Regression in Multiple CCNE1

Amplified Models

MRT-55811 induced tumor regression in CCNE1 amplified ovarian model

MRT-55811 induced tumor regression in CCNE1 amplified breast model

Tumor Volume (mm3)

mean +/- SEM

1000

300

100

Ovarian

0 7 14 21

Days of treatment

CCNE1

CCNE1 Protein Expression

Rel. to β-Actin

125

100

pCDK2 Protein Expression

Rel. to β-Actin

pCDK2 (T160)

125

100

Vehicle

MRT-55811

AZD8421

1000

Tumor Volume (mm3)

mean +/- SEM

300

100

Breast

0 7 14 21

Days of treatment

CCNE1

CCNE1 Protein Expression

Rel. to β-Actin

150

125

100

pCDK2 Protein Expression

Rel. to β-Actin

pCDK2 (T160)

125

100

Vehicle

MRT-55811

AZD8421

21-day efficacy study in OVSAHO CDX

21-day efficacy study in HCC1569 CDX

AZD8421 dosing selected based on 2024 AACR Annual Meeting disclosure

‌CCNE1 Program

First-in-class, highly selective CCNE1-targeting molecular glue degrader;

previously undruggable target

CCNE1 amplified cell lines (ovarian, endometrial, gastric, breast) are sensitive to CCNE1 degradation

RB-dependent activity indicates on-target effects and differentiates from clinical-stage CDK2 inhibitors

Monotherapy efficacy seen in CCNE1-amplified cancer models in vivo, consistent with on-target downstream pathway suppression

Disclaimer

Monte Rosa Therapeutics Inc. published this content on April 21, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on April 21, 2026 at 23:15 UTC.