Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that recruit an E3 ligase to a target protein to facilitate ubiquitination and subsequent degradation of that protein. While the field of targeted degraders is still relatively young, the potential for this modality to become a differentiated and therapeutic reality is strong, such that both academic and pharmaceutical institutions are now entering this interesting area of research. In this article, we describe a broadly applicable process for identifying degrader hits based on the serine/threonine kinase TANK-binding kinase 1 (TBK1) and have generalized the key structural elements associated with degradation activities. Compound 3i is a potent hit (TBK1 DC = 12 nM, D = 96%) with excellent selectivity against a related kinase IKKε, which was further used as a chemical tool to assess TBK1 as a target in mutant K-Ras cancer cells.

The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure-activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure-degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

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New synthetic routes for the preparation of five-coordinate zirconium and titanium complexes featuring tridentate diamidoamine ligands were developed. Zirconium dichloride complexes, [(Mes)N(CH 2) 2 NR(CH 2) 2 N(Mes)]ZrCl 2 (R = H, SiMe 3), were synthesized via a onestep toluene elimination reaction. Analogous titanium dichloride complexes, [(Mes)N(CH 2) 2 NR(CH 2) 2 N(Mes)]TiCl 2 (R = H, SiMe 3), were prepared using a one-step amine elimination reaction. Table of Contents iv List of Tables vi List of Figures vii Chapter 1. Introduction 1 Chapter 2. Results and Discussion 2.1. Preparation and Characterization of Triamines (Mes)NH(CH 2) 2 NR(CH 2) 2 NH(Mes), R = H, SiMe 3 2.2. Preparation and Characterization of Five-Coordinate Zirconium Complexes 2.3. Preparation and Characterization of Five-Coordinate Titanium Complexes 2.4. Description of the Crystal Structures of 10, 11, and 13 Chapter 3. Concluding Remarks Chapter 4. Experimental Section 4.1. Reagents 4.2. General Considerations 4.3. Preparation of Starting Materials 4.3.1. Preparation of Zr(NMe 2) 4 , 1 4.3.2. Preparation of Ti(NMe 2) 4 , 2 4.3.3. Preparation of Ti(NMe 2) 2 Cl 2 , 3 4.3.4. Preparation of LiNEt 2 , 4 4.3.5. Preparation of Ti(NEt 2) 4 , 5 4.3.6. Preparation of Ti(NEt 2) 2 Cl 2 , 6 4.4. Preparation of Triamines (Mes)NH(CH 2) 2 NR(CH 2) 2 NH(Mes), R = H, SiMe 3 4.4.1. Preparation of (Mes)NH(CH 2) 2 NH(CH 2) 2 NH(Mes), Mes = Mesityl, 7 4.4.2. Preparation of (Mes)NH(CH 2) 2 N(SiMe 3)(CH 2) 2 NH(Mes), Mes = Mesityl, 8 4.5. Preparation of Five-Coordinate Zirconium Bis(dimethylamido) Complexes v 4.5.1. Preparation of [(Mes)N(CH 2) 2 NH(CH 2) 2 N(Mes)]Zr(NMe 2) 2 , Mes = Mesityl, 9 4.6. Preparation of Five-Coordinate Zirconium Dichloride Complexes 4.6.1. Preparation of [(Mes)N(CH 2) 2 NH(CH 2) 2 N(Mes)]ZrCl 2 , Mes = Mesityl, 10 4.6.1.1. Reaction of 9 with SiMe 3 Cl 4.6.1.2. Toluene Elimination Reaction 4.6.2. Preparation of [(Mes)N(CH 2) 2 N(SiMe 3)(CH 2) 2 N(Mes)]ZrCl 2 , Mes = Mesityl, 11 4.7. Preparation of Five-Coordinate Titanium Dichloride Complexes 4.7.1. Preparation of [(Mes)N(CH 2) 2 NH(CH 2) 2 N(Mes)]TiCl 2 , Mes = Mesityl, 12 4.7.1.1. Amine Elimination Reaction with 3 4.7.1.2. Amine Elimination Reaction with 6 4.7.2. Preparation of [(Mes)N(CH 2) 2 N(SiMe 3)(CH 2) 2 N(Mes)]TiCl 2 , Mes = Mesityl, 13 4.8. Description of the X-ray Structural Analyses Chapter 5. References Vita

The mammalian SWI/SNF complex catalyzes the remodeling of chromatin through the helicase activity of two mutually-exclusive, paralogous subunits, BRG1 and BRM. BRG1 is frequently mutated in cancer and its inactivation results in a cellular dependence on BRM. Despite the attractiveness of BRM as a synthetic lethal therapeutic target, the selective inhibition of BRM represents a considerable challenge due to the high degree of homology between BRM and BRG1. Furthermore, published data indicate that achieving such selectivity is likely essential to afford an acceptable therapeutic index. We sought to mimic the synthetic lethality observed in BRG1-mutant cancers by identifying proteolysis-targeting chimera (PROTAC®) molecules capable of selectively degrading BRM via trimeric complex formation with the von Hippel-Lindau (VHL) E3 ligase. In this disclosure, we report our initial discovery of potent and selective chimeric BRM-degrader molecules which exhibit BRM DC50 values <1 nM and BRG1/BRM DC50 ratios >25. Importantly, selective BRM degradation can be achieved in the absence of selective PROTAC® binding (BRG1/BRM Kd ratios <2). Global ubiquitin mapping and proteome profiling reveal no unexpected off-target activity of the selective BRM PROTAC® degraders. Treatment of a panel of NSCLC cell lines with a representative degrader molecule resulted in enhanced growth inhibition in BRG1-mutant relative to BRG1-wild-type cell lines. We also demonstrate that intermittent intravenous administration of an optimized BRM PROTAC® degrader exhibited strong in vivo modulation of pharmacodynamic biomarkers and afforded tumor growth inhibition in several BRG1-mutant xenograft models. Our study thus highlights the ability to transform a non-selective BRM-binding ligand into a selective and efficacious in vivo BRM PROTAC® degrader. Citation Format: Michael Berlin, Jennifer Cantley, Jing Wang, Mark Bookbinder, Gregory Cadelina, Emily Chan, Huifen Chen, Xin Chen, Kim Davenport, Tharu Fernando, Debbie Gordon, Brian Hamman, Roy Haskell, Alexey Ishchenko, Donald S. Kirkpatrick, Jonathan Maher, Mark Merchant, John Moffat, Alicia Morgan, An Nguyen, Jennifer Pizzano, Connor Quinn, Christopher M. Rose, Emma Rousseau, Vijay Sethuraman, Leanna Staben, Catherine Wilson, Xiaofen Ye, Fabio Broccatelli, Robert Yauch, Peter S. Dragovich. Selective, chemically-induced degradation of BRM (SMARCA2) enables in vivo efficacy in BRG1 (SMARCA4)-deficient xenograft tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5687.