An Open Label, Escalating Multiple Dose Study to Evaluate the Safety, Toxicity, Pharmacokinetics, and Preliminary Activity of BTX-1188 in Subjects With Advanced Malignancies

This is a multicenter, open label, nonrandomized, sequential dose escalation, multiple dose study designed to evaluate the safety, toxicity, and pharmacokinetics (PK) as well as preliminary efficacy of BTX-1188 orally administered in subjects with advanced malignancies.

Start Date24 Jan 2022

Sponsor / Collaborator

BioTheryX, Inc.

100 Clinical Results associated with GSPT1 x IKZF1 x IKZF3

100 Translational Medicine associated with GSPT1 x IKZF1 x IKZF3

0 Patents (Medical) associated with GSPT1 x IKZF1 x IKZF3

Literatures (Medical) associated with GSPT1 x IKZF1 x IKZF3

27 Mar 2025·Journal of Medicinal Chemistry

Monoselective Histone Deacetylase 6 PROTAC Degrader Shows In Vivo Tractability

Article

Author: Olaoye, Olasunkanmi O. ; Moriggl, Richard ; de Araujo, Elvin D. ; Sedighi, Abootaleb ; Abdallah, Diaaeldin I. ; Yu, Wenlong ; Hariri, Pearla ; Pölöske, Daniel ; Gunning, Patrick T. ; Garcha, Harsimran K.

Herein, we report a potent HDAC6 PROTAC, TO-1187, which selectively degrades HDAC6 in cellulo and demonstrates in vivo efficacy. The design of TO-1187 was achieved by linking our previously reported HDAC6 inhibitor, TO-317, to the cereblon (CRBN) E3 ligase ligand, pomalidomide. TO-1187 achieved monoselective HDAC6 degradation in human multiple myeloma cells, MM.1S, with a D_max of 94% and a DC₅₀ of 5.81 nM after 6 h. Importantly, at concentrations up to 25 μM, TO-1187 exhibited no cellular degradation of other HDACs. Proteomic evaluation confirmed a highly selective proteome-wide degradation profile, with HDAC6 the only protein observed to be depleted. Notably, TO-1187 did not impact the abundance of well-known CRBN neosubstrates, like IKZF1, IKZF3, CK1α, SALL4, and GSPT1. In vivo evaluation confirmed that TO-1187 efficiently degraded HDAC6 in mouse tissues, measured 6 h after intravenous injection. In summary, TO-1187 represents a viable candidate for advanced preclinical evaluation of HDAC6 biology.

25 Jan 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Trends in Neosubstrate Degradation by Cereblon-Based Molecular Glues and the Development of Novel Multiparameter Optimization Scores

Q1 · MEDICINE

Article

Author: Verma, Isha ; Weiss, Dahlia R. ; Edwards, Jacob T. ; Chekler, Eugene L. P. ; Szewczyk, Suzanne M.

Molecular glues enable the degradation of previously "undruggable" proteins via the recruitment of cereblon (CRBN) to the target. One major challenge in designing CRBN E3 ligase modulating compounds (CELMoDs) is the selectivity profile toward neosubstrates, proteins recruited by CRBN E3 ligase agents for degradation. Common neosubstrates include Aiolos, Ikaros, GSPT1, CK1α, and SALL4. Unlike achieving potency and selectivity for traditional small molecule inhibitors, reducing the degradation of these neosubstrates is complicated by the ternary nature of the complex formed between the protein, CRBN, and CELMoD. The standard guiding principles of medicinal chemistry, such as enforcing hydrogen bond formation, are less predictive of degradation efficiency and selectivity. Disclosed is an analysis of our glutarimide CELMoD library to identify interpretable chemical features correlated to selectivity profiles and general cytotoxicity. Included is a simple multiparameter optimization function using only three parameters to predict whether molecules will have undesired neosubstrate activity.

01 Dec 2023·ChemBioChem

A Degron Blocking Strategy Towards Improved CRL4^CRBN Recruiting PROTAC Selectivity**

Article

Author: Roumeliotis, Theodoros I ; McAndrew, P Craig ; van Montfort, Rob L M ; Wah Hak, Laura Chan ; Mitsopoulos, Costas ; Collins, Ian ; Sialana, Fernando J ; Warne, Justin ; Chopra, Rajesh ; Hahner, Tamas ; Cabry, Marc P ; O'Hanlon, Jack A ; Caldwell, John J ; Le Bihan, Yann-Vaï ; Pierrat, Olivier A ; Choudhari, Jyoti ; Wang, Hannah Z ; Scarpino, Andrea ; Bouguenina, Habib ; Burke, Rosemary ; Stubbs, Mark ; Sadok, Amine

AbstractSmall molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo‐substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4CRBN neo‐substrates to attenuate and indeed remove this monovalent degradation function in well‐known CRL4CRBN molecular glues degraders, namely CC‐885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9‐A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC‐induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.

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