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

作者: Shi, Dongping ; Zamiri, Alaleh ; Son, Yeon Sung ; Sung, Ki Woon ; Bae, Tae Hyun ; Najy, Abdo J. ; Kim, Hyeong-Reh Choi ; Kregel, Steven ; Kim, Seongho ; Cher, Michael L. ; Mun, Su Ran ; Jang, Hyejeong ; Kwon, Yong Tae ; Heath, Elisabeth I. ; Kwon, Ha Kyoung ; Pham, Tri M.

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.

2025-01-01·Cell Reports

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

Article

作者: 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.

2025-01-01·Discovery Medicine

The Ubiquitin Code in Disease Pathogenesis and Progression: Composition, Characteristics and its Potential as a Therapeutic Target

Review

作者: Kim, Su Bin ; Lee, Su Jin ; Ji, Chang Hoon ; Kim, Hye Yeon ; Lee, Ji Su ; Kwon, Yong Tae

Conjugation of substrate proteins with ubiquitin (Ub), a 76 amino acid protein, was discovered as the first major translational modification responsible for protein degradation. Ubiquitination occurs as a cascade among ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligases (E3) enzymes that transfer and covalently conjugate Ub to the lysine (Lys) residue and α-amino group in methionine (Met) residues of substrates. Following the initial conjugation, Ub itself then undergoes ubiquitination via its seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) and N-terminal methionine (M1). These possible sites of Ub polymerization/assembly result in a significantly diverse and numerous set of linkage types and lengths, including homotypic, mixed and/or branched chains, which provoke distinct cellular responses via their proteolytic and non-proteolytic functions. We overview here the multiplicity of ubiquitin code with a particular focus on linkage-specific roles in biological processes, especially in the pathogenesis and progression of diseases such as cancer, neurodegeneration, and immune disorders. We will also discuss the possibility and ongoing efforts of modulating the ubiquitin code as a therapeutic strategy in drug development, including targeted protein degradation (TPD).

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药物(靶点)	适应症	全球最高研发状态

ATC-101(AUTOTAC Bio)	阿尔茨海默症更多	临床前
AB-14 ( TDP43 )	肌萎缩侧索硬化更多	临床前
ATC-324 ( AR )	前列腺癌更多	临床前
ATC-602	糖尿病更多	临床前
ATC-503	脓毒症更多	临床前