ROLE OF CYNLIN-DEPENDENT KINASES INHIBITORS IN CELL

GROWTH REGULATION AND CANCER

Thanh-Binh Nancy Le

OVERVIEW

First: Introduce the Biological Review

Second: Review the Drug Design

Third: Demonstrate the Experiment

BIOLOGICAL REVIEW

WHAT IS CYCLIN-DEPENDENT KINASES?

Cyclin-dependent kinases (CDKs) are a family of serine-threonine protein kinases.

WHAT IS CYCLIN?

WHICH ARE THE CYCLINS AND CDKS THAT INVOLVE IN CELL-

CYCLE PHASE?

WHAT IS CYCLIN-DEPENDENT KINASES INHIBITOR (CKI)?

TWO MAJOR CLASSES OF CKI FAMILY

WHAT IS THE MOLECULAR STRUCTURE OF P21?

•Six β -strands

•Five α-helices

CRYSTAL STRUCTURE OF P21

WHAT IS THE FUNCTION OF P21 IN CELL CYCLE REGULATION?

Control and consequent loss of cell cycle checkpoints.

Stop cell cycle to induce differentiation and senescence.

THE MECHANISM OF P21 REGULATION

WHAT WILL HAPPEN IF P21 IS MUTATED?

Oncogenic mutation. Higher barrier for conformational change. Not undergo conformational change. Rearrange Loop 4 Increase the lifetime of the active state. Results in continuation of signal for cell

growth.

WHAT DISEASE CAUSED BY POINT MUTATIONS IN P21 ?

LUNG CANCER

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

MYELOID LEUKEMIA

THYROID TUMOR

COLON TUMOR

ADENOCARCINOMA TUMOR OF THE PANCREAS

DRUG DESIGNS

2-ANILINO-4-(THIAZOL-5-YL) PYRIMIDINE (1PXN).

Ki = 0.07uM

Length =298

HOW DOES 1PXN BINDS TO THE PROTEIN?

1PXN bind to CDK2 at four ligands active site:

HYDROXYFASUDIL (2ERZ)

Ki=2.2uM

Length=351

HOW DOES 2ERZ BIND TO THE PROTEIN?

A B

1-(5-ISOQUINOLINESULFONYL)-2-METHYLPIPERAZINE (1YDR)

Ki=3uM

Length=350

HOW DOES 1YDR BIND THE PROTEIN?

BALANOL ANALOG 1 (1REJ)

Ki=3nMKi=5nM

Length =350

HOW DOES THE 1REJ BIND THE PROTEIN ?

STAUROSPORINE (1STC)

Ki=8nM

Length=350

HOW DOES 1STC BIND TO THE PROTEIN?

NU2058 (1H1P)

Ki=12uM

Length=303

HOW DOES 1H1P BIND TO THE PROTEIN?

HOW ARE EACH DRUG DIFFERENT FROM ONE ANOTHER?

EXPERIMENT

PURPOSE OF THE LAB

•Understand • Competitive binding of the Cyclin-Kinase

Inhibitors CDK2 over the substrate.

•How different functional groups in the inhibitors play the inhibitor binding.

METHOD• Get CDK2 protein from pdb bank.• Creating prmtop files • Create t-leap• Calculate the relative binding

affinities of CDK inhibitors.• Using MM-PBSA in the Amber

software

THE

ENDTHANK YOU FOR

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