ACBI3

ACBI3 : panKRAS Degrader (PROTAC)

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

KRAS (Mutant:pan variants)

Degrader (PROTAC)

up to 100 nM

In Vitro Validations

Uniprot ID: P01116

Target Class: Kinase

Target SubClass: Ras Family

Potency: Kd

Potency Value: 6 nM

Potency Assay: SPR for ternary complex with VHL

PDB ID for probe-target interaction (3D structure): 8QU8, 8QVU

Target aliases:

GTPase KRas, RASK2, KRAS2, KRAS, RASK_HUMAN, c-Ki- ...

DOI Reference: 10.1126/science.adm8684

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay, off target (cells): The degradation selectivity of ACBI3 was assessed by whole cell proteomics MS analysis of GP2d cells treated with ACBI3 or the inactive stereoisomer cis-ACBI3 (50 nM). HRAS (log2 fold change -0.0006, -logP 0.001) and NRAS (log2 fold change -0.12, -logP 0.52) levels are not significantly affected.

Potency assay, off target (cells): Proliferation inhibition data was assessed for 240 cancer cell lines for ACBI3

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

ACBI3 is a very well characterized pan KRAS degrader, developed by leaders in the field of targeted protein degradation. Sparing HRAS and NRAS, this probe is useful for addressing specific KRAS mutants when others are not present in a cell line, or for the simultaneous degradation of multiple KRAS mutants. The substance is well optimized for use in cell-based experiments, but is not fully optimized for in vivo use. The authors have, however, provided detailed formulation methods which can be used to achieve acceptable exposure, making in vivo experiments possible.

(last updated: 10 Oct 2025 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

While there is strong evidence of KRAS degradation, ternary complex, and pathway inhibition, data supporting direct cellular engagement of KRAS was not provided.

(last updated: 13 Oct 2025 )

SERP+ Ratings

In Cell Rating

In Model Organisms

SERP+ Comments:

Highly selective pan-KRAS degrader shown through proteomics data, broadly active across cancer cell lines containing mutant KRAS versus wild-type. High efflux could be mitigated with the use of zosuquidar. Evidence of ternary complex formation observed through CryoEM. Hook effect observed in cells above 100 nM. In vivo degradation of pan-KRAS demonstrated. Plasma concentrations of ACBI3 reach DC50 at 30 mg/kg and is systematically tolerated as indicated by no change in mouse weight over 14 days. Suppresses oncogenic KRAS protein levels in vivo beyond its pharmacokinetic presence.

(last updated: 6 Feb 2026 )