Cancer Biology
Cancerous cells are abnormal cell growth, eventually forming a mass of tissue known as a tumor. Cancer cells can spread to other parts of the body through the bloodstream or lymphatic system, a process known as metastasis. Cancer cells have the ability metastasis e rapidly to tissues and organs beyond where the tumor originated causing the patient to succumb to death. One of the major hallmarks of cancer metastasis is the reprogramming of energy metabolism pathway.
Pyruvate Kinase M2 (PKM2) plays a critical role in cancer metastasis by switching to an inactive dimer that causes the upstream accumulation of glycolytic intermediates, promoting tumorigenesis. PKM2 has been identified as a diagnostic biomarker for various cancers, such as renal cell carcinoma and gastrointestinal, lung, ovarian, and pancreatic cancer.
PKM2's switch from active tetrameric from to less active dimeric form is governed by many factors, majorly due to the presence of Post-Translational Modifications (PTMs). These PTMs have been identified to cause structural alterations at binding site of fructose 1,6-bisphosphate (FBP) leading to its eviction. Identifying these structural changes can aid to restore the active tetrameric form of the protein.
Knowledge-based drug discovery was employed to design a virtual library of small molecule activators targeting PKM2. Critical features were identified from the experimentally known PKM2 activators and design compounds that would significantly confer a stable structural and functional edge over the known compounds at the preclinical stage.
The final selected molecules could stabilize the functionally relevant tetrameric conformation in the dynamic environment.