Advances in targeting ‘undruggable’ transcription factors with small molecules

Henley, Matthew J.; Koehler, Angela N.

doi:10.1038/s41573-021-00199-0

Cited by 227 publications

(177 citation statements)

References 291 publications

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“…The large HOX/MEIS/PBX complex could offer several interfaces to be targeted to decrease their oncogenic function in leukemic patients. However, the development of smallmolecule inhibitors of protein-protein interactions is challenging, especially for transcription factors, as surfaces are typically smooth and do not present the deep pockets present in enzyme active sites, making the development of small-molecule inhibitors more difficult [72][73][74][75]. This may be the case for the PREP1-PBX or the MEIS1-PBX interaction surface.…”

Section: The Meis1-pbx1 and The Prep1-pbx Interaction Surfacementioning

confidence: 99%

MEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy

Blasi

Bruckmann

2021

JDB

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Recently MEIS1 emerged as a major determinant of the MLL-r leukemic phenotype. The latest and most efficient drugs effectively decrease the levels of MEIS1 in cancer cells. Together with an overview of the latest drugs developed to target MEIS1 in MLL-r leukemia, we review, in detail, the role of MEIS1 in embryonic and adult hematopoiesis and suggest how a more profound knowledge of MEIS1 biochemistry can be used to design potent and effective drugs against MLL-r leukemia. In addition, we present data showing that the interaction between MEIS1 and PBX1 can be blocked efficiently and might represent a new avenue in anti-MLL-r and anti-leukemic therapy.

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Section: The Meis1-pbx1 and The Prep1-pbx Interaction Surfacementioning

confidence: 99%

MEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy

Blasi

Bruckmann

2021

JDB

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“…In cancer cells, actin remodelling has also been found to aid evasion from NK killing. For example, accumulation of actin at the immune synapse in breast cancer cells encountering NK limited the accumulation of the cytotoxic molecule granzyme B in the cancer cells, protecting them from lysis and resulting in lowered apoptosis of the tumour cell (149). The cancer cell lines used in this study (149) exhibited different levels of actin accumulation at the immune synapse, and it was suggested that compared to epithelial-like cancer cells, mesenchymal-like cancer cells had a higher capacity to generate actin accumulation at the immune synapse, thus contributing to differential and greater resistance to NK killing.…”

Section: Spatio-temporal Cytoskeletal Co-ordination Of Nk Cytolysismentioning

confidence: 99%

“…For example, accumulation of actin at the immune synapse in breast cancer cells encountering NK limited the accumulation of the cytotoxic molecule granzyme B in the cancer cells, protecting them from lysis and resulting in lowered apoptosis of the tumour cell (149). The cancer cell lines used in this study (149) exhibited different levels of actin accumulation at the immune synapse, and it was suggested that compared to epithelial-like cancer cells, mesenchymal-like cancer cells had a higher capacity to generate actin accumulation at the immune synapse, thus contributing to differential and greater resistance to NK killing. The cellular cytoskeletal dynamics on both sides of the immune synapse, which influences the contact-dependent nature of NK-mediated killing, appears to play a pivotal role in the success or failure of NK cell elimination of target cells.…”

Section: Spatio-temporal Cytoskeletal Co-ordination Of Nk Cytolysismentioning

confidence: 99%

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

2021

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Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.

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“…5b). Additional TFs have also been targeted by TPD molecules 20,77,78 , such as degraders for AR 38,[79][80][81] and ER [82][83][84][85][86] that have entered into clinical trials. With the exception of BCL6 which has few reported Ub sites, MAPD correctly predicts the high degradability of most TF PROTAC targets (Fig.…”

Section: Mapd Predicts Proteome-wide Degradabilitymentioning

confidence: 99%

“…Unlike traditional inhibitors that target the catalytic binding site on a POI, degraders can induce protein degradation by binding to non-catalytic sites 11,17,18 . Therefore, previously undruggable proteins, such as transcription factors (TF), can be targeted by degraders 19,20 . For example, the FDA-approved immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide [21][22][23][24][25][26][27][28] induce degradation of transcription factors IKZF1 and IKZF3 by recruiting them to CRBN 25,26,[29][30][31][32] , the substrate recognition subunit of the E3 ubiquitin ligase complex CUL4-RBX1-DDB-CRBN 33 .…”

Section: Introductionmentioning

confidence: 99%

Machine learning modeling of protein-intrinsic features predicts tractability of targeted protein degradation

Zhang

Burman

Chen

et al. 2021

Preprint

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Targeted protein degradation (TPD) has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell's endogenous protein degradation machinery. However, the susceptibility of proteins for targeting by TPD approaches, termed "degradability", is largely unknown. Recent systematic studies to map the degradable kinome have shown differences in degradation between kinases with similar drug-target engagement, suggesting yet unknown factors influencing degradability. We therefore developed a machine learning model, MAPD (Model-based Analysis of Protein Degradability), to predict degradability from protein features that encompass post-translational modifications, protein stability, protein expression and protein-protein interactions. MAPD shows accurate performance in predicting kinases that are degradable by TPD compounds (auPRC=0.759) and is likely generalizable to independent non-kinase proteins. We found five features with statistical significance to achieve optimal prediction, with ubiquitination potential being the most predictive. By structural modeling, we found that E2-accessible ubiquitination sites, but not lysine residues in general, are particularly associated with kinase degradability. Finally, we extended MAPD predictions to the entire proteome to find 964 disease-causing proteins, including 278 cancer genes, that may be tractable to TPD drug development.

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Advances in targeting ‘undruggable’ transcription factors with small molecules

Cited by 227 publications

References 291 publications

MEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy

MEIS1 in Hematopoiesis and Cancer. How MEIS1-PBX Interaction Can Be Used in Therapy

NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton

Machine learning modeling of protein-intrinsic features predicts tractability of targeted protein degradation

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