Ashok V. Purandare

Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1).

This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound 7b is a potent, selective inhibitor of CARM1.

Structural Basis for Carm1 Inhibition by Indole and Pyrazole Inhibitors

CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.

Optimization of pyrazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)

Design, synthesis, and SAR development led to the identification of the potent, novel, and selective pyrazole based inhibitor (7f) of Coactivator Associated Arginine Methyltransferase (CARM1).

Benzo[d]imidazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)—Hit to Lead studies

Hit to Lead optimization and SAR development led to the identification of the potent and selective benzo[d]imidazole inhibitor (17b) of Co-activator Associated Arginine Methyltransferase (CARM1).

Synthesis of chiral α- substituted β-hydroxy acid derivatives on solid support

Abstract Enantioselective aldol condensation using solid supported chiral auxiliary was used for the synthesis of α-substituted-β-hydroxy acid and ester. The solid phase synthesis proceeded with high degree of enatioselectivity, as is observed in solution chemistry.

Antagonists of CCR4 as immunomodulatory agents.

The chemokine receptor CCR4 is broadly expressed on cells of the immune system. It is known to play a central role in T cell migration to the thymus, and T cell maturation and education. In addition, CCR4 is known to modulate T cell migration to several sites of inflammation in the body, including the skin, and lungs. It is best known as a drug target for airway inflammation and atopic dermatitis, but cells expressing CCR4 are found in many inflammatory diseases. CCR4 small molecule antagonists have not yet reached the clinic, but at least one has been validated in an in vivo model. Here we review the current status of structurally novel CCR4 receptor antagonists.

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need. Mol Cancer Ther; 14(10); 2167–74. ©2015 AACR.

Solid-phase synthesis of diverse' heterocycles

A novel and efficient solid-phase synthetic methodology for constructing ‘diverse’ heterocycles from ortho-fluoronitrobenzoic acid has been developed.

Solid phase synthesis of unsymmetrical secondary amines—Application to the synthesis of arylethanolamines and arylpropanolamines

Abstract A novel and simple solid phase synthesis of unsymmetrical secondary amines was developed. The general methodology was applied to the synthesis of arylethanolamines and arylpropanolamines.

Pyrrolo[1,2-f]triazines as JAK2 inhibitors: Achieving potency and selectivity for JAK2 over JAK3.

SAR studies of pyrrolo[1,2-f]triazines as JAK2 inhibitors is presented. Achieving JAK2 inhibition selectively over JAK3 is discussed.