Discovery of fully synthetic FKBP12-mTOR molecular glues

Chemical Science, Год журнала: 2025, Номер 16(10), С. 4256 - 4263

Опубликована: Янв. 1, 2025

Molecular glues are a new drug modality with the potential to engage otherwise undruggable targets. However, rational discovery of molecular for desired targets is major challenge and most known have been discovered by serendipity. Here we present first fully synthetic FKBP12-mTOR glues, which were from FKBP-focused, target-unbiased ligand library. Our biochemical screening >1000 in-house FKBP ligands yielded one hit that induced dimerization FKBP12 FRB domain mTOR. The crystal structure ternary complex revealed targeted similar surface on compared natural product rapamycin but radically different interaction pattern. Structure-guided optimization improved potency 500-fold, led compounds initiate FKBP12-FRB formation in cells. results show targeting flat surfaces can be focused support use as versatile presenter protein glues.

Язык: Английский

---

Decoding the functional impact of the cancer genome through protein–protein interactions

Nature reviews. Cancer, Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

Язык: Английский

---

Routes to molecular glue degrader discovery

Trends in Biochemical Sciences, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

---

The “three body solution”: Structural insights into molecular glues

Current Opinion in Structural Biology, Год журнала: 2025, Номер 91, С. 103007 - 103007

Опубликована: Фев. 26, 2025

Язык: Английский

---

Design and Synthesis of 7-(N-Aryl Pyrrolidinyl) Indoles as Potential DCAF15 Binders

Reactions, Год журнала: 2025, Номер 6(1), С. 20 - 20

Опубликована: Март 7, 2025

We describe the design and synthesis of a series 7-(N-aryl pyrrolidinyl) indoles oxo-analogs as isosteric mimics DCAF15 binder E7820, well-known member aryl sulfonamides known SPLAMs. The functionalization C-7 in was achieved by metal-catalyzed CH-activation with unexpected results. Binding assays revealed pyrrolidine N-aryl carboxylic acid analog to be equally active E7820.

Язык: Английский

---

Evaluation of molecular glue-induced neo-Protein-Protein Interaction with a cell lysate-based TR-FRET assay

Опубликована: Март 1, 2025

Язык: Английский

---

Mining the CRBN Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 9, 2024

Abstract The CRL4 CRBN ubiquitin ligase is leveraged by molecular glue degraders, small molecules that reprogram specificity to induce degradation of clinically relevant neosubstrate proteins. Known neosubstrates share a generalizable β-hairpin G-loop recognition motif, yet systematic exploration the target landscape still pending. Through computational mining human proteome using structure-based approaches, we predict over 1,400 CRBN-compatible proteins across diverse classes, identify novel mechanisms through structurally differentiated helical motifs and surface mimicry, validate 22 representative with clinical implications. This work broadens space, redefines rules for establishes platform elimination challenging drug targets repurposing next-generation degraders.

Язык: Английский

---

Functional Investigations of p53 Acetylation Enabled by Heterobifunctional Molecules

ACS Chemical Biology, Год журнала: 2024, Номер 19(9), С. 1918 - 1929

Опубликована: Сен. 9, 2024

Post-translational modifications (PTMs) dynamically regulate the critical stress response and tumor suppressive functions of p53. Among these, acetylation events mediated by multiple acetyltransferases lead to differential target gene activation subsequent cell fate. However, our understanding these is incomplete due to, in part, inability selectively control p53 acetylation. We recently developed a heterobifunctional small molecule system, AceTAG, direct acetyltransferase p300/CBP for targeted protein cells. Here, we expand AceTAG leverage PCAF/GCN5 apply tools investigate functional consequences human cancer demonstrate that recruitment or results distinct differentiated transcriptional activities. Further, show chemically induced hotspot mutants increased stabilization enhancement activity. Collectively, studies utility investigations

Язык: Английский

---

Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond

Neurotherapeutics, Год журнала: 2024, Номер unknown, С. e00499 - e00499

Опубликована: Дек. 1, 2024

Язык: Английский

---

Discovery of DCAF16 Binders for Targeted Protein Degradation

ACS Chemical Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Conventional small-molecule drugs primarily operate by inhibiting protein function, but this approach is limited when proteins lack well-defined ligand-binding pockets. Targeted degradation (TPD) offers an alternative harnessing cellular pathways to eliminate specific proteins. Recent studies have expanded the potential of TPD identifying additional E3 ligases, with DCAF16 emerging as a promising candidate for facilitating through both proteolysis-targeting chimera (PROTAC) and molecular glue mechanisms. In study, we revisited previously reported compound discovered that it covalently binds DCAF16. We further optimized into FKBP12-targeting PROTAC, MC-25B. This PROTAC engages at cysteines C177-179, leading nuclear-localized FKBP12. demonstrated versatility recruiter degrading endogenous Compared first-generation DCAF16-based which was derived from fragment electrophile, recruiter-based exhibits improved proteome-wide selectivity.

Язык: Английский

---