Delving into the Latest Updates on Autotac Bio, Inc. with Synapse

Overview

Tags

Nervous System Diseases

Other Diseases

Endocrinology and Metabolic Disease

AUTOphagy-Targeting Chimera (AUTOTAC)

Drug conjugates

Proteolysis-targeting chimeras (PROTAC)

Disease domain score

A glimpse into the focused therapeutic areas

Technology Platform

Most used technologies in drug development

Targets

Most frequently developed targets

Disease Domain	Count

Nervous System Diseases	11
Endocrinology and Metabolic Disease	7
Neoplasms	6
Infectious Diseases	1

Top 5 Drug Type	Count

AUTOphagy-Targeting Chimera (AUTOTAC)	11
Drug conjugates	9
Proteolysis-targeting chimeras (PROTAC)	1

Top 5 Target	Count

TAU(Microtubule-associated protein tau)	3
p53(Tumor protein p53)	2
TTR(Transthyretin)	2
AR(Androgen Receptor)	2
ATE1(arginyltransferase 1)	1

AbstractGenetic alterations play a pivotal role in various human diseases, particularly cancer. The androgen receptor (AR) is a crucial transcription factor driving prostate cancer progression across all stages. Current AR-targeting therapies utilize competitive AR antagonists or pathway suppressors. However, therapy resistance often emerges due to AR mutations and AR splice variants, such as AR-v7. To overcome this, we developed ATC-324, an AR degrader using the innovative protein degradation technology platform AUTOphagy-TArgeting Chimera (AUTOTAC). ATC-324 was designed to comprise enzalutamide, an AR inhibitor, as a target-binding ligand and YT 6-2, a ligand of the autophagy receptor p62/SQSTM1, as an autophagy-targeting ligand. ATC-324 induces the formation of the AR/p62 complex, leading to autophagy–lysosomal degradation of AR. Importantly, ATC-324 effectively degrades AR mutants frequently detected in prostate cancer and codegrades AR-v7 as a heterodimer with full-length AR. ATC-324 reduces nuclear AR levels and downregulates the target gene expression of AR and AR-v7, leading to cytotoxicity in AR-positive prostate cancer cells. We also provide evidence of the therapeutic potential of ATC-324 in vivo as well as ex vivo bone organ culture. Moreover, ATC-324 remains potent in enzalutamide-resistant prostate cancer cells. These results demonstrate the potential of the AUTOTAC platform to target previously considered undruggable proteins and overcome certain drug resistance mechanisms.Significance: The characterization of an AUTOTAC-based degrader capable of inducing autophagic degradation of wild-type and mutated androgen receptors demonstrates the potential of this approach for targeting castration-resistant prostate cancer and overcoming drug resistance.

01 Jan 2025·Cell Reports

The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses

Article

Author: Kim, Sung Tae ; Cho, Eun Hye ; Ahn, Jin-Hyun ; Kwon, Yong Tae ; Han, Dohyun ; Kim, Daeho ; Sung, Ki Sa ; Lee, Yoon Jee ; Lee, Gee Eun ; Jung, Chan Hoon ; Kim, Dong Hyun ; Son, Yeon Sung

The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway. In the resolution phase of sterile immune responses, DNA-dependent protein kinase (DNA-PK) senses cytosolic mtDNA and activates N-terminal (Nt-) arginylation by ATE1 R-transferases. The substrates of Nt-arginylation include the molecular chaperone BiP/GRP78 retrotranslocated from the endoplasmic reticulum (ER). R-BiP, the Nt-arginylated species of BiP, is associated with cytosolic mtDNA to accelerate its targeting to autophagic membranes for lysosomal degradation. Thus, cytosolic mtDNA activates the N-degron pathway to facilitate its own degradation and form a negative feedback loop, by which the cell can turn off sterile immune responses at the right time.

01 Feb 2024·Autophagy

Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform

Article

Author: Kwon, Yong Tae ; Yoon, Dabin ; Lee, Jihoon ; Bae, Eun-Jin ; Sung, Ki Woon ; Park, Da-Ha ; Suh, Young Ho

Parkinson disease (PD) characterized by dopaminergic neuronal loss is caused by aggregation of misfolded SNCA/α-synuclein. We recently developed autophagy-targeting chimera (AUTOTAC), a targeted protein degradation (TPD) technology based on the macroautophagy/autophagy-lysosome pathway (ALP). In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates. The autophagy-targeting ligand (ATL) of ATC161 was designed to allosterically activate the autophagy receptor SQSTSM1/p62 (sequestosome 1), a key step for targeting SNCA aggregates to the phagophore. The lysosomal degradation of SNCA aggregates by ATC161 acutely occurs at DC50 of 100-500 nM with no significant off-target degradation of monomeric SNCA. ATC161 protects cells from DNA and mitochondrial damage by SNCA aggregates. In PD model mice, oral administration of ATC161 decreases the level of SNCA aggregates and their propagation across brain regions, which mitigates glial inflammatory responses and improves muscle strength and locomotive activity. An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases.

100 Deals associated with Autotac Bio, Inc.

Login to view more data

100 Translational Medicine associated with Autotac Bio, Inc.

Login to view more data

Corporation Tree

Boost your research with our corporation tree data.

login

or

view full example data

Boost your research with our corporation tree data.

Pipeline

Pipeline Snapshot as of 05 Feb 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Discovery

4

17

Preclinical

Login to view more data

Current Projects

Drug(Targets)	Indications	Global Highest Phase

AB-16 ( α-synuclein )	Parkinson Disease More	Preclinical
ATC-402	Muscular Dystrophy, Duchenne More	Preclinical
ATC-601	Obesity More	Preclinical
ATC-102 ( TAU )	Alzheimer Disease More	Preclinical
ATC-503	Sepsis More	Preclinical