4.7 Review

Current progress and novel strategies that target CDK12 for drug discovery

相关参考文献

注意:仅列出部分参考文献,下载原文获取全部文献信息。
Article Chemistry, Medicinal

DYRK1A inhibitors for disease therapy: Current status and perspectives

Tong Liu et al.

Summary: DYRK1A, a conserved protein kinase, plays essential roles in various biological processes and is associated with Down syndrome, neurodegenerative diseases, cancer, and diabetes. The development of DYRK1A inhibitors has seen a rapid increase in recent years, providing new directions for future therapeutic research.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2022)

Article Biochemistry & Molecular Biology

THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors

Pavithra Shyamsunder et al.

Summary: This study found that the CDK12 inhibitor THZ531 has a cytotoxic effect on multiple myeloma cells and downregulates genes involved in DNA repair pathways. Combining THZ531 with DNA-PK inhibitor or PARP inhibitor synergistically induces cell death, and combination treatment of THZ531 with Olaparib significantly reduces tumor burden in animal models.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Review Biotechnology & Applied Microbiology

PROTAC targeted protein degraders: the past is prologue

Miklos Bekes et al.

Summary: Targeted protein degradation (TPD) is a new therapeutic modality that can tackle disease-causing proteins which are difficult to target with conventional small molecules. PROTAC molecules, utilizing the ubiquitin-proteasome system to degrade target proteins, has achieved clinical proof-of-concept and attracted significant industry activity. Future directions include identifying target classes suitable for TPD, expanding the use of ubiquitin ligases for precision medicine, and extending the modality beyond oncology.

NATURE REVIEWS DRUG DISCOVERY (2022)

Article Oncology

Analysis of CDK12 alterations in a pan-cancer database

Elizabeth Pan et al.

Summary: CDK12 alterations are rare events across hematologic and solid tumor malignancies. They represent a clinically distinct molecular cancer subtype which may have increased responsiveness to checkpoint inhibition. Prospective studies are warranted to investigate checkpoint inhibition in CDK12-altered tumors.

CANCER MEDICINE (2022)

Article Urology & Nephrology

Circulating tumour DNA reveals genetic traits of patients with intraductal carcinoma of the prostate

Jinge Zhao et al.

Summary: The study found genetic alterations differences between patients with and without intraductal carcinoma of the prostate (IDC-P), with higher proportions of DNA repair pathway and AR pathway alterations in IDC-P carriers. For IDC-P carriers, TP53 mutation was associated with shorter castration-resistant-free survival, and BRCA2 alteration was related to rapid PSA progression in patients receiving abiraterone treatment.

BJU INTERNATIONAL (2022)

Article Hematology

Response and resistance to CDK12 inhibition in aggressive B-cell lymphomas

Jing Gao et al.

Summary: This study found that both Mantle Cell Lymphoma (MCL) and Diffuse Large B-cell Lymphoma (DLBCL) are highly sensitive to transcription-targeting drug THZ531. THZ531 inhibits lymphoma growth by suppressing oncogenic transcriptional programs. The study also discovered that resistance to THZ531 can be overcome by using EZH2 inhibitors.

HAEMATOLOGICA (2022)

Article Chemistry, Medicinal

3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders

Radek Jorda et al.

Summary: 3,5,7-Trisubstituted pyrazolo [4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases, and their structural modifications have led to novel nanomolar inhibitors with strong antiproliferative activity. Crystal structure analysis confirmed the competitive mode of inhibition and biochemical and cellular assays demonstrated the expected mechanism of action through induction of apoptosis and degradation of cyclin K. This compound exhibits a dual mechanism of action as both a kinase inhibitor and a molecular glue.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

Article Pharmacology & Pharmacy

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Xiaosa Chang et al.

Summary: The study successfully designed the first dual-target small-molecule inhibitor targeting both PARP1 and BRD4, showing important cross relation and synthetic lethal effect in breast cancer global network. The inhibitor exhibited good activity and therapeutic potential in breast cancer cells.

ACTA PHARMACEUTICA SINICA B (2021)

Review Oncology

Targeting CDK12 for Cancer Therapy: Function, Mechanism, and Drug Discovery

Hui Liu et al.

Summary: The role of CDK12 in carcinogenesis and cancer prevention is not well understood, but a comprehensive understanding of CDK12 could greatly facilitate the development of new strategies for cancer treatment and prevention.

CANCER RESEARCH (2021)

Editorial Material Oncology

CDK12 Deficiency and the Immune Microenvironment in Prostate Cancer

Tamara L. Lotan et al.

Summary: CDK12 inactivation in prostate cancer may generate fusion-associated neoantigens and elicit immune responses. The T-cell immune microenvironment of CDK12-deficient prostate cancers showed an increase in immunosuppressive CD4(+) FOXP3(-) T cells compared to CDK12-proficient controls.

CLINICAL CANCER RESEARCH (2021)

Article Chemistry, Medicinal

Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma

Baishan Jiang et al.

Summary: BSJ-01-175 is the first selective CDK12/13 covalent inhibitor with in vivo efficacy, exhibiting potent inhibition of RNA polymerase II phosphorylation and downregulation of CDK12-targeted genes in cancer cells.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2021)

Article Oncology

CDK12 inhibition enhances sensitivity of HER2+breast cancers to HER2-tyrosine kinase inhibitor via suppressing PI3K/AKT

Hui Li et al.

Summary: CDK12, co-amplified with HER2, can sensitize or resensitize HER2-positive breast cancer to anti-HER2 TKIs and suppress PI3K/AKT signaling. Patients with CDK12 amplification respond less sensitively to anti-HER2 treatment compared to those without, leading to a significantly shortened progression-free survival.

EUROPEAN JOURNAL OF CANCER (2021)

Article Immunology

CDK12 Promotes Cervical Cancer Progression through Enhancing Macrophage Infiltration

Bikang Yang et al.

Summary: CDK12 expression in cervical cancer is closely related to disease progression and poor prognosis, promoting cancer cell progression by regulating the immune microenvironment through macrophage infiltration. Nuclear import of CDK12, mediated by TNPO1, may be a new therapeutic target in oncology.

JOURNAL OF IMMUNOLOGY RESEARCH (2021)

Article Biochemistry & Molecular Biology

Discovery and resistance mechanism of a selective CDK12 degrader

Baishan Jiang et al.

Summary: CDK12 is a promising therapeutic target for regulating DNA damage response genes transcription, but selective small molecule development has been hindered by its homology with other transcriptional CDKs. A CDK12-specific degrader, BSJ-4-116, was successfully designed and characterized, which selectively degraded CDK12 and resulted in premature cleavage and poly(adenylation) of DDR genes.

NATURE CHEMICAL BIOLOGY (2021)

Editorial Material Biochemistry & Molecular Biology

Novel Mechanisms of Molecular Glue-Induced Protein Degradation

Shanique Alabi

BIOCHEMISTRY (2021)

Article Chemistry, Medicinal

Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery

Guoqiang Dong et al.

Summary: Targeted protein degradation through molecular glues is a promising area in drug discovery, offering unique biological activities and physicochemical properties. While classical molecular glue degraders have been serendipitously identified, rational discovery and design strategies are now rapidly emerging.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Article Pathology

Predicted Immunogenicity of CDK12 Biallelic Loss-of-Function Tumors Varies across Cancer Types

Andrew Elliott et al.

Summary: CDK12 biallelic inactivation is associated with focal tandem duplications (FTDs) and high fusion-associated neoantigen load in certain cancer types like prostate and ovarian. However, low fusion rates were found in some CDK12-biLOF tumors with concurrent mismatch repair deficiency. Fusion rate and fusion-associated neoantigen load linked to CDK12-biLOF may help identify responders to immune checkpoint inhibitor therapy in select cancers.

JOURNAL OF MOLECULAR DIAGNOSTICS (2021)

Article Cell Biology

Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer

Sebastian M. Dieter et al.

Summary: In this study, a novel treatment option for metastatic colorectal cancer (CRC) was identified through drug screening against patient-derived CRC spheroids. The compound NCT02 was found to induce proteasomal degradation of CCNK and CDK12, leading to decreased proliferation of CRC cells. Interestingly, sensitivity to CCNK/CDK12 degradation was associated with TP53 deficiency and consensus molecular subtype 4, highlighting the potential of drug-induced proteolysis for difficult-to-treat cancers.

CELL REPORTS (2021)

Editorial Material Urology & Nephrology

CDK12 Mutation in Advanced Prostate Cancer: A Marker for Clinical Subtype?

Xiao Wang et al.

EUROPEAN UROLOGY (2020)

Article Urology & Nephrology

Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer

Melissa A. Reimers et al.

EUROPEAN UROLOGY (2020)

Review Pharmacology & Pharmacy

Targeting autophagy-related protein kinases for potential therapeutic purpose

Honggang Xiang et al.

ACTA PHARMACEUTICA SINICA B (2020)

Article Biochemistry & Molecular Biology

Rapid block of pre-mRNA splicing by chemical inhibition of analog-sensitive CRK9 inTrypanosoma brucei

Ujwala Gosavi et al.

MOLECULAR MICROBIOLOGY (2020)

Article Multidisciplinary Sciences

CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

Zheng Fan et al.

SCIENCE ADVANCES (2020)

Article Pathology

Low expression of CDK12 in gastric cancer is correlated with advanced stage and poor outcome

Meijia Liu et al.

PATHOLOGY RESEARCH AND PRACTICE (2020)

Article Clinical Neurology

Cyclin-dependent kinase 12 (CDK12) in chordoma: prognostic and therapeutic value

Pichaya Thanindratarn et al.

EUROPEAN SPINE JOURNAL (2020)

Article Chemistry, Medicinal

Discovery of MFH290: A Potent and Highly Selective Covalent Inhibitor for Cyclin-Dependent Kinase 12/13

Yao Liu et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

Article Multidisciplinary Sciences

The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

Mikolaj Slabicki et al.

NATURE (2020)

Article Biochemistry & Molecular Biology

Rational discovery of molecular glue degraders via scalable chemical profiling

Cristina Mayor-Ruiz et al.

NATURE CHEMICAL BIOLOGY (2020)

Article Biochemistry & Molecular Biology

CDK12 globally stimulates RNA polymerase II transcription elongation and carboxyl-terminal domain phosphorylation

Michael Tellier et al.

NUCLEIC ACIDS RESEARCH (2020)

Review Pharmacology & Pharmacy

CDK12: a potential therapeutic target in cancer

Fatemeh Emadi et al.

DRUG DISCOVERY TODAY (2020)

Review Chemistry, Medicinal

PROTAC: A promising technology for cancer treatment

Xin Zhou et al.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2020)

Article Medicine, Research & Experimental

CDK12 and PAK2 as novel therapeutic targets for human gastric cancer

Hui Liu et al.

THERANOSTICS (2020)

Article Multidisciplinary Sciences

CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

Malgorzata Krajewska et al.

NATURE COMMUNICATIONS (2019)

Article Biochemistry & Molecular Biology

CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling

Hee-Joo Choi et al.

EMBO REPORTS (2019)

Article Medicine, Research & Experimental

Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma

Ian Bayles et al.

JOURNAL OF CLINICAL INVESTIGATION (2019)

Review Biochemistry & Molecular Biology

The PROTAC technology in drug development

Yutian Zou et al.

CELL BIOCHEMISTRY AND FUNCTION (2019)

Review Biochemistry & Molecular Biology

Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium

Arno L. Greenleaf

TRANSCRIPTION-AUSTIN (2019)

Article Biochemistry & Molecular Biology

Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer

David A. Quigley et al.

Article Chemistry, Medicinal

Structure-Based Design of Selective Noncovalent CDK12 Inhibitors

Jeffrey W. Johannes et al.

CHEMMEDCHEM (2018)

Article Medicine, Research & Experimental

Dinaciclib induces immunogenic cell death and enhances anti-PD1-mediated tumor suppression

Dewan Md Sakib Hossain et al.

JOURNAL OF CLINICAL INVESTIGATION (2018)

Article Biochemistry & Molecular Biology

CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling

Kate L. Henry et al.

SCIENCE SIGNALING (2018)

Article Biochemistry & Molecular Biology

Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors

Yang Gao et al.

CELL CHEMICAL BIOLOGY (2018)

Article Biochemistry & Molecular Biology

CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion

Jerry F. Tien et al.

NUCLEIC ACIDS RESEARCH (2017)

Article

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Hana Paculová et al.

TUMOR BIOLOGY (2017)

Review Cell Biology

The emerging roles of CDK12 in tumorigenesis

Hana Paculova et al.

CELL DIVISION (2017)

Article Oncology

Combined venetoclax and alvocidib in acute myeloid leukemia

James Bogenberger et al.

ONCOTARGET (2017)

Article Biochemistry & Molecular Biology

Cdk12 is essential for embryonic development and the maintenance of genomic stability

H-C Juan et al.

CELL DEATH AND DIFFERENTIATION (2016)

Review Oncology

Role and therapeutic potential of CDK12 in human cancers

Rosaria Chila et al.

CANCER TREATMENT REVIEWS (2016)

Article Biochemistry & Molecular Biology

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Tinghu Zhang et al.

NATURE CHEMICAL BIOLOGY (2016)

Article Biochemistry & Molecular Biology

Engineering an analog-sensitive CDK12 cell line using CRISPR/Cas

Bartlomiej Bartkowiak et al.

BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS (2015)

Article Chemistry, Medicinal

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs

Concepcion Sanchez-Martinez et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2015)

Article Biochemistry & Molecular Biology

Integrative Clinical Genomics of Advanced Prostate Cancer

Dan Robinson et al.

Article Multidisciplinary Sciences

Heterochromatin remodeling by CDK12 contributes to learning in Drosophila

Lixia Pan et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2015)

Article Biochemistry & Molecular Biology

Expression, Purification, and Identification of Associated Proteins of the Full-length hCDK12/CyclinK Complex

Bartlomiej Bartkowiak et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2015)

Article Oncology

A phase I trial of flavopiridol in relapsed multiple myeloma

Craig C. Hofmeister et al.

CANCER CHEMOTHERAPY AND PHARMACOLOGY (2014)

Article Oncology

NF-κB, an Active Player in Human Cancers

Yifeng Xia et al.

CANCER IMMUNOLOGY RESEARCH (2014)

Article Chemistry, Medicinal

Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties

Mathieu Bibian et al.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2013)

Article Developmental Biology

The regulation of glial-specific splicing of Neurexin IV requires HOW and Cdk12 activity

Floriano Rodrigues et al.

DEVELOPMENT (2012)

Review Multidisciplinary Sciences

The DNA damage response and cancer therapy

Christopher J. Lord et al.

NATURE (2012)

Article Multidisciplinary Sciences

Functional genomics identifies therapeutic targets for MYC-driven cancer

Masafumi Toyoshima et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2012)

Review Cell Biology

Cyclin K goes with Cdk12 and Cdk13

Jiri Kohoutek et al.

CELL DIVISION (2012)

Review Biochemistry & Molecular Biology

Phosphorylation mechanism and structure of serine-arginine protein kinases

Gourisankar Ghosh et al.

FEBS JOURNAL (2011)

Review Biochemistry & Molecular Biology

NF-κB inducing kinase: A key regulator in the immune system and in cancer

Yee Mon Thu et al.

CYTOKINE & GROWTH FACTOR REVIEWS (2010)

Letter Cell Biology

Cyclin-dependent kinases: a family portrait

Marcos Malumbres et al.

NATURE CELL BIOLOGY (2009)

Article Biochemistry & Molecular Biology

CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases

K. Bettayeb et al.

ONCOGENE (2008)

Review Oncology

Comparing antibody and small-molecule therapies for cancer

Kohzoh Imai et al.

NATURE REVIEWS CANCER (2006)

Article Biotechnology & Applied Microbiology

Monoclonal antibody successes in the clinic

JM Reichert et al.

NATURE BIOTECHNOLOGY (2005)

Article Biochemistry & Molecular Biology

The crystal structure of human CDK7 and its protein recognition properties

G Lolli et al.

STRUCTURE (2004)