Research

Life Sciences & Biotechnology

Title :	Preclinical development of IGF1R selective allosteric small molecule inhibitor(s) and characterization of newly identified allosteric inhibitor binding pocket in IGF1R
Area of research :	Life Sciences & Biotechnology
Principal Investigator :	Dr. Mohd Jamal Dar, Csir-Indian Institute Of Integrative Medicine (Csir-iim)
Timeline Start Year :	2024
Timeline End Year :	2027
Contact info :	jamal@iiim.ac.in

Details

Executive Summary :

Hypothesis- The IGF1R pathway is commonly dysregulated in many human cancers particularly in breast cancer. Therapeutic approaches to target IGF1R face many challenges. One of the major challenges is that IGF1R shares very high degree of sequence and structural homology with insulin receptor (IR), thus targeting IGF1R inevitably impairs glucose homeostasis resulting in hyperglycemia. Need of the time is to identify IGF1R specific inhibitors (allosteric inhibitors) that can only target IGF1R and spare all other proteins in the cell, IR in particular. Over the last few years we published very exciting papers on IGFIR in reputed cell biology journals like Journal of Cell Science (Bhat etal., 2022), IGF-Growth Factor Research (Bano etal. 2020), BBA-Molecular Cell Research (Gayatri etal., 2018). We generated a library of GFP-fusion constructs of IGF1R and observed how IGF1R is translocating into the nucleus, identified a unique allosteric inhibitor binding pocket in IGF1R, and a stretch of four critical residues within this pocket involved in regulating kinase activity of IGF1R. In this proposal, we aim to structurally characterize this binding pocket, and we are interested in the preclinical development of compound identified as allosteric inhibitor of IGF1R using in-silico approaches. Since nuclear IGF1R is seen to be responsible for drug resistance in cancers. Therefore, we are also interested in identifying candidate proteins that are differentially interacting with nuclear IGF1R which is involved in anti-cancer drug resistance. Rationale- We conceived this project with three different verticals or approaches (which are both dependent and independent). First, we want to develop the allosteric small molecule inhibitor(s) of IGF1R that can specifically target IGF1R mediated malignancies. Second, we are interested in solving the crystal structure of IGF1R kinase domain wildtype (along with the proposed inhibitor) and IGF1R kinase domain mutant (E1056G) to examine their impact on IGF1R structural integrity. Third, since nuclear IGF1R is involved in anti-cancer drug resistance, we are interested in identifying proteins that are differentially interacting with nuclear IGF1R thereby regulating its nuclear functions. The fact that we have been continuously working on IGF1R for the last seven years now, therefore, all the objectives proposed in this project are doable and achievable in stipulated time Significance to the field of research- Deliverables envisaged from this project are- 1. Discovery of small molecule allosteric inhibitor(s) of IGF1R- as a novel anti-cancer agent for the treatment of breast cancer where IGF1R is recognized as a promising drug target 2. Structural studies of allosteric inhibitor with IGF1R kinase domain (wildtype-mutant) will serve as proof of the concept how this allosteric inhibitor impacts IGF1R mediated carcinogenesis 3. Identifying nuclear binding partners and nuclear functions of IGF1R

Co-PI:

Dr. RAMAJAYAN P Csir-Indian Institute Of Integrative Medicine (Csir-Iiim), Post Bag 3, Canal Road,Jammu And Kashmir,Jammu-180001, Dr. SHOWKAT RASHID Csir-Indian Institute Of Integrative Medicine (Csir-Iiim), Post Bag 3, Canal Road,Jammu And Kashmir,Jammu-180001