Subramanya Hosahalli

Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: Wild type and mutant (L1196M) active compounds with unique binding mode.

We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7b, 7 m and 7 n demonstrate excellent potencies in biochemical and cellular assays. X-ray crystal structure of one of the compounds (7 k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif.

X-ray structure of PTP1B in complex with a new PTP1B inhibitor.

Protein tyrosine phosphatase 1B (PTP1B) is a prototype non receptor cytoplasmic PTPase enzyme that has been implicated in regulation of insulin and leptin signaling pathways. Studies on PTP1B knockout mice and PTP1B antisense treated mice suggested that inhibition of PTP1B would be an effective strategy for the treatment of type II diabetes and obesity. Here we report the X-ray structure of PTP1B in complex with compound IN1834-146C (PDB ID 4I8N). The crystals belong to P3121 space group with cell dimensions (a = b = 87.89 Å, c = 103.68 Å) diffracted to 2.5 Å. The crystal structure contained one molecule of protein in the asymmetric unit and was solved by molecular replacement method. The compound engages both catalytic site and allosteric sites of PTP1B protein. We described the molecular interaction of the compound with the active site residues of PTP1B in this crystal structure report.

Abstract 671: Identification of potent BET bromodomain inhibitors for treatment of cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression. Histone lysine acetylation is one of the most abundant epigenetic modifications central to control of gene transcription. Bromodomains are the only known readers of this specific lysine acetylation code, playing an important role in transcriptional regulation of diverse cellular processes such as inflammatory gene expression, mitosis and viral/host interactions. Recently, the human BET family bromodomains which consists of BRD2, BRD3, BRD4 and BRDT has emerged as new druggable target class for the development of specific protein interaction inhibitors, enabling a novel strategy for the development of new therapies for various diseases. Here we report the identification of potent BET bromodomain inhibitors using structure based drug design principle. Multiple distinct series of compounds have been identified with low nM potency in biochemical binding assay. Crystal structures of BRD4 in complex with hit compounds have been solved to assist in optimization. The lead compounds showed very good cell based activity and favorable ADME properties. The compounds demonstrated dose dependent inhibition of c-Myc expression confirming the mechanism of action. Further optimization of these compounds and profiling in relevant pre-clinical disease models is in progress. Citation Format: Sanjita Sasmal, Rajeev Kumar Shrimali, Chandrasekhar Abbineni, Kamala Kumari Arumalla, Anirudha Lakshminarasimhan, Karthikeyan Narasingapuram Arumugam, Nirbhay Kumar Tiwari, Narasimha K. Rao, Aravind AB, Subramanya Hosahalli. Identification of potent BET bromodomain inhibitors for treatment of cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 671. doi:10.1158/1538-7445.AM2013-671