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Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML.

ABSTRACT: The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription.

SUBMITTER: Brand M

PROVIDER: S-EPMC6444916 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML.

Brand Matthias M Jiang Baishan B Bauer Sophie S Donovan Katherine A KA Liang Yanke Y Wang Eric S ES Nowak Radosław P RP Yuan Jingting C JC Zhang Tinghu T Kwiatkowski Nicholas N Müller André C AC Fischer Eric S ES Gray Nathanael S NS Winter Georg E GE

Cell chemical biology 20181227 2

The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immed ...[more]

PMID: 30595531

Similar Datasets

Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

Project description:The design of selective small-molecules is often stymied by similar ligand binding pockets. Here we report the first cyclin-dependent kinase 6 (CDK6) degrader, BSJ-03-123, that uses phthalimide-conjugation to exploit protein-interface determinants to achieve proteome-wide degradation selectivity. Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and coupling acute degradation with transcriptomics and phosphoproteomics enabled dynamic mapping of the immediate role of CDK6 in coordinating signaling and transcription.

2018-11-20 | GSE116187 | GEO

Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

Project description:Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

| PRJNA477657 | ENA

CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML.

Project description:Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukaemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase-dependent and kinase-independent effects, have been suggested as an alternative therapeutic option. We show that the efficacy of the CDK6-specific protein degrader BSJ-03-123 varies among AML subtypes and depends on the low expression of the INK4 proteins p16INK4A and p18INK4C. INK4 protein levels are significantly elevated in KMT2A-MLLT3+ cells compared to RUNX1-RUNX1T1+ cells, contributing to the different CDK6 degradation efficacy. We demonstrate that CDK6 complexes containing p16INK4A or p18INK4C are protected from BSJ-mediated degradation and that INK4 levels define the proliferative response to CDK6 degradation. These findings define INK4 proteins as predictive markers for CDK6 degradation-targeted therapies in AML.

| S-EPMC8946512 | biostudies-literature

Selective degradation of CDK6 by a palbociclib based PROTAC.

Project description:Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation.

| S-EPMC6487213 | biostudies-literature

CDK6 Inhibition: A Novel Approach in AML Management.

Project description:Acute myeloid leukemia (AML) is a complex disease with an aggressive clinical course and high mortality rate. The standard of care for patients has only changed minimally over the past 40 years. However, potentially useful agents have moved from bench to bedside with the potential to revolutionize therapeutic strategies. As such, cell-cycle inhibitors have been discussed as alternative treatment options for AML. In this review, we focus on cyclin-dependent kinase 6 (CDK6) emerging as a key molecule with distinct functions in different subsets of AML. CDK6 exerts its effects in a kinase-dependent and -independent manner which is of clinical significance as current inhibitors only target the enzymatic activity.

| S-EPMC7178035 | biostudies-literature

CDK6 degradation is counteracted by p16INK4A and p18INK4C in AML

Project description:Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase dependent and kinase independent effects, have been suggested as alternative therapeutic option. We show that efficacy of the CDK6 specific protein degrader BSJ-03-123 varies among AML subtypes and depends on low expression of the INK4 proteins p16INK4A and p18INK4C. INK4 protein levels are significantly elevated in MLL-AF9+ compared to AML1-ETO+ cells, contributing to the different CDK6 degradation efficacy. We demonstrate that CDK6 complexes containing p16INK4A or p18INK4C are protected from BSJ-mediated degradation and that INK4 levels define the proliferative response to CDK6 degradation. These findings define INK4 proteins as predictive marker for CDK6 degradation – targeted therapies in AML.

2022-04-04 | PXD032216 | Pride

Optimized mucin-selective enrichment strategy to probe the mucinome

Project description:Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. Previously, we developed a mucin-selective enrichment strategy by employing a catalytically inactive mucinase (StcE) conjugated to solid support. While this method was effective, it suffered from low throughput and high sample requirements. Further, we recently introduced a new mucinase (SmE) and demonstrated it has complementary recognition patterns to StcE. Here, we optimized our previous enrichment method to increase throughput and lower sample input amounts while maintaining mucin selectivity and enhancing glycopeptide signal. We also compare the ability of different mucinases, lectins, and mucin binding domains to enrich mucins from various cell lines and human serum. Overall, we demonstrate that our improved method StcE effectively isolates more mucin-domain glycoproteins, resulting in a high number of O-glycopeptides, which will allow for enhanced analysis of the mucinome.

2024-04-10 | PXD046534 | Pride

HCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML.

Project description:BackgroundLeukaemia stem cells (LSCs) are responsible for the initiation, maintenance, and recurrence of acute myeloid leukaemia (AML), an aggressive haematological malignancy associated with drug resistance and relapse. Identifying therapeutic LSC targets is critical to curing AML.MethodsBioinformatics databases were used to identify therapeutic LSC targets. The conditional knockout mice were used to analyse the role of HCK in leukaemogenesis or normal haematopoiesis. Colony-forming assays, cell counting, and flow cytometry were used to detect the viability and function of leukaemia cells. RT-PCR, western blotting, and RNA sequencing were used to detect mRNA and protein expression.ResultHCK is expressed at higher levels in LSCs than in haematopoietic stem cells (HSCs), and high HCK levels are correlated with reduced survival time in AML patients. Knockdown of HCK leads to cell cycle arrest, which results in a dramatic decrease in the proliferation and colony formation in human AML cell lines. Moreover, HCK is required for leukemogenesis and leukaemia maintenance in vivo and in vitro. HCK is necessary for the self-renewal of LSCs during serial transplantation and limiting dilution assay. The phenotypes resulting from HCK deficiency can be rescued by CDK6 overexpression in the human cell line. RNA sequencing and gene expression have demonstrated that HCK may sustain cell cycle entry and maintain the self-renewal ability of LSCs through activating the ERK1/2-c-Myc-CDK6 signalling axis. In contrast, HCK deletion does not affect normal haematopoiesis or haematopoietic reconstruction in mice.ConclusionsHCK maintains the self-renewal of leukaemia stem cells via CDK6 in AML and may be an ideal therapeutic target for eradicating LSCs without influencing normal haematopoiesis.

| S-EPMC8223385 | biostudies-literature

CDK6 binds and promotes the degradation of the EYA2 protein.

Project description:Cyclin-dependent kinase 6 (Cdk6) is a D-Cyclin-activated kinase that is directly involved in driving the cell cycle through inactivation of pRB in G₁ phase. Increasingly, evidence suggests that CDK6, while directly driving the cell cycle, may only be essential for proliferation of specialized cell types, agreeing with the notion that CDK6 also plays an important role in differentiation. Here, evidence is presented that CDK6 binds to and promotes degradation of the EYA2 protein. The EYA proteins are a family of proteins that activate genes essential for the development of multiple organs, regulate cell proliferation, and are misregulated in several types of cancer. This interaction suggests that CDK6 regulates EYA2 activity, a mechanism that could be important in development and in cancer.

| S-EPMC3925736 | biostudies-literature

Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.

Project description:A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.

| S-EPMC6790125 | biostudies-literature

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