Nx-2127, a Degrader of BTK and IMiD Neosubstrates, for the Treatment of B-Cell Malignancies

Robbins, Daniel W.; Kelly, Aileen; Tan, May; McIntosh, Joel; Wu, Jiayue; Konst, Zef; Kato, Daisuke; Peng, Ge; Mihalic, Jeff; Weiss, Dahlia R.; Pérez, Luz Marina Jaramillo; Tung, Jennifer; Kolobova, Anna; Borodovsky, Sasha; Rountree, Ryan B.; Tenn-McClellan, Austin; Noviski, Mark; Ye, Jordan; Basham, Steve; Ingallinera, Timothy; McKinnell, Jenny; Karr, Dane E.; Powers, Janine; Guiducci, Cristiana; Sands, Arthur

doi:10.1182/blood-2020-141461

Cited by 33 publications

(19 citation statements)

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“…Further, NX-5948 is capable of crossing the blood-brain barrier in animal models. ( Robbins et al, 2020 ; Robbins et al, 2021 ). Though initial results are still forthcoming, the potential of these PROTACs in clinical trials is noteworthy.…”

Section: Protacs Targeted Towards Treatment Of Various Types Of Drug ...mentioning

confidence: 99%

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Burke

Smith

Zheng

2022

Front. Cell Dev. Biol.

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Cancer drug resistance presents a major barrier to continued successful treatment of malignancies. Current therapies inhibiting proteins indicated in cancer progression are consistently found to lose efficacy as a result of acquired drug resistance, often caused by mutated or overexpressed protein targets. By hijacking the cellular ubiquitin-proteasome protein degradation machinery, proteolysis-targeting chimeras (PROTACs) offer an alternative therapeutic modality to cancer treatments with various potential advantages. PROTACs specific for a number of known cancer targets have been developed in the last 5 years, which present new options for remission in patients with previously untreatable malignancies and provide a foundation for future-generation compounds. One notable advantage of PROTACs, supported by evidence from a number of recent studies, is that they can overcome some of the resistance mechanisms to traditional targeted therapies. More recently, some groups have begun researching the use of PROTACs to successfully degrade mutated targets conferring cancer resistance against first-line treatments. In this review, we focus on analyzing the developments in PROTACs geared towards cancer resistance and targets that confer it in the search for new and successful therapies.

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Section: Protacs Targeted Towards Treatment Of Various Types Of Drug ...mentioning

confidence: 99%

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Burke

Smith

Zheng

2022

Front. Cell Dev. Biol.

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“…Although the resistance could be addressed by developing third- or fourth generations of EGFR inhibitors, new drug resistance will emerge. PROTAC technology has shown certain advantages in overcoming drug resistance against cancer drug targets due to the degradation of target proteins with reduced evolutionary pressure of target mutations ( Shibata et al, 2017 ; Burslem et al, 2018 ; Burslem et al, 2019 ; Flanagan et al, 2019 ; Cheng et al, 2020 ; Robbins et al, 2020 ; Liu et al, 2021 ; Robbins et al, 2021 ). However, new mechanisms of drug resistance may occur ( Zhang L. et al, 2019 ).…”

Section: Drug Resistance In Targeted Protein Degradationmentioning

confidence: 99%

Key Considerations in Targeted Protein Degradation Drug Discovery and Development

Qin¹,

Dai

Wang

2022

Front. Chem.

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Targeting proteins’ enzymatic functions with small molecule inhibitors, as well as functions of receptor proteins with small-molecule agonists and antagonists, were the major forms of small-molecule drug development. These small-molecule modulators are based on a conventional occupancy-driven pharmacological approach. For proteome space traditionally considered undruggable by small-molecule modulators, such as enzymes with scaffolding functions, transcription factors, and proteins that lack well-defined binding pockets for small molecules, targeted protein degraders offer the opportunity to drug the proteome with an event-driven pharmacological approach. A degrader molecule, either PROTAC or molecular glue, brings the protein of interest (POI) and E3 ubiquitin ligase in close proximity and engages the ubiquitin-proteasome system (UPS), the cellular waste disposal system for the degradation of the POI. For the development of targeted protein degraders to meet therapeutic needs, several aspects will be considered, namely, the selective degradation of disease-causing proteins, the oral bioavailability of degraders beyond Lipinski’s rule of five (bRo5) scope, demands of new E3 ubiquitin ligases and molecular glue degraders, and drug resistance of the new drug modality. This review will illustrate several under-discussed key considerations in targeted protein degradation drug discovery and development: 1) the contributing factors for the selectivity of PROTAC molecules and the design of PROTACs to selectively degrade synergistic pathological proteins; 2) assay development in combination with a multi-omics approach for the identification of new E3 ligases and their corresponding ligands, as well as molecular glue degraders; 3) a molecular design to improve the oral bioavailability of bRo5 PROTACs, and 4) drug resistance of degraders.

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“…NX-5948 that target BTK for degradation and show promise in preclinical evaluations (Robbins et al, 2020).…”

Section: Alternative Btk Targeting Approachesmentioning

confidence: 99%

“…Nevertheless, targeted degradation of BTK could emerge as another tool in the arsenal for treating various immunological diseases. There are emerging PROTACs, including NX-2127 and NX-5948 that target BTK for degradation and show promise in preclinical evaluations ( Robbins et al, 2020 ).…”

Section: Alternative Btk Targeting Approachesmentioning

confidence: 99%

Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK

Kueffer

Joseph

Andreotti

2021

Front. Cell Dev. Biol.

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Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies.

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Nx-2127, a Degrader of BTK and IMiD Neosubstrates, for the Treatment of B-Cell Malignancies

Cited by 33 publications

References 0 publications

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Key Considerations in Targeted Protein Degradation Drug Discovery and Development

Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK

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