TAK-243

Inhibitor of UBA1

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

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Information

UBA1

Inhibitor

0.01, 0.10 or 1.00 μM

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Probe Availability:

In Vitro Validations

Uniprot ID: P22314

Target Class: Other post-translational modification

Target SubClass: Ubiquitin-conjugating enzyme

Potency: Kd

Potency Value: >0.75 nM

Potency Assay: E1–UBL-dependent pyrophosphate exchange (PPiX) activity

PDB ID for probe-target interaction (3D structure): 5TR4, 5L6J

Structure-activity relationship: yes

Target aliases:

Ubiquitin-like modifier-activating enzyme 1, UBE1, ...

DOI Reference: 10.1038/nm.4474

Uniprot ID: P22314

Target Class: Other post-translational modification

Target SubClass: Ubiquitin-conjugating enzyme

Potency: IC50

Potency Value: 1 ± 0.2 nM

Potency Assay: UBCH10 E2 transthiolation assay

PDB ID for probe-target interaction (3D structure): --

Target aliases:

Ubiquitin-like modifier-activating enzyme 1, UBE1, ...

DOI Reference: 10.1038/nm.4474

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Probe Selectivity in Vitro:

TAK-243 has significant biochemical inhibitory activity against closely related E1 ubiquitin-like activating enzymes Fat10-activating enzyme (UBA6; 7 ± 3 nM) and NEDD8-activating enzyme (NAE; 28 ± 11 nM) but has better biochemical selectivity for UBA1 over SUMO-activating enzyme (SAE; 850 ± 180 nM), ISG15-activating enzyme (UBA7; 5,300 ± 2,100 nM), and autophagy-activating enzyme (ATG7; >10,000 nM).

Outside target family: Tested on Novascreen Receptor Panel (at 1 µM TAK-243; minimal findings) and carbonic anhydrases. Inhibitory activities of 1 µM TAK-243 against 319 kinases were measured at Reaction Biology Corporation (Malvern, PA) with no significant findings.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

TAK-243 is a potent inhibitor of UAE which demonstrates complete inhibition of cellular ubiquitylation and sub-micromolar anti-proliferative activity against multiple cancer cell lines. Robust antitumor activity has been achieved in murine subcutaneous xenograft studies via IV or SC administration.

(last updated: 20 May 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

TAK-243 is a potent inhibitor of UBA1 with cellular activities consistent with the proposed mechanism of action. TAK-243 shows anti-tumor activity in mouse xenograft studies at doses at or below the maximum tolerated dose. Although TAK-243 is a potent inhibitor of the UBA1-related enzymes UBA6 and UBA3 (NEDD8-activating enzyme), these off-target activities are reported not to contribute to the anti-tumor efficacy of TAK-243. Users should consider whether activity against UBA6 or UBA3 will impact their own studies.

TAK-243 may be suitable for interrogating Uba1 in yeast as well as in mammalian cells: structural studies show that the yeast enzyme is inhibited by the same mechanism as the mammalian enzyme. Potency and selectivity in yeast is not yet established.

(last updated: 11 Jun 2021 )

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 31 May 2023 )