ITC is one of India’s leading hotel chains with over 120 hotels. It offers a wide range of accommodation options from budget hotels to luxury properties. The company has a unique business model that focuses on asset righting and is building a future-ready portfolio.
In addition to hotels, ITC has a large FMCG business that provides value-based products. The company’s FMCG business contributes to more than 26% of its segment EBITDA. The company has a focus on bringing quality brands to the Indian market and believes in a sustainable supply chain. ITC is also investing in agri-value chain and has expanded its MAARS program to nine states and over 6,00,000 farmers.
The company’s cigarette business is positioned to grow further with stability in the tax regime and increasing consumption in the country. ITC expects to expand its footprint in the tier-2 and tier-3 markets through new launches and partnerships with other brands.
Itc bet proteins regulate diverse transcriptional programs by binding acetylated histones and other ligands. The inhibition of human BET BDs by small molecules has generated significant interest as a therapeutic strategy. However, the limited number of clinical compounds with activity against human BET BDs has raised concerns about the safety of this approach.
To identify BET inhibitors with selective activity, we conducted a series of counter-screen experiments against the yeast CaBdf1 BD1. The resulting compounds displayed high selectivity against the BD2 of CaBdf1 and reduced potency against the corresponding BD1 of human BET, with IC50 values in the micromolar range (Fig. 2a). To assess the binding energy of each compound, isothermal calorimetry (ITC) measurements were performed. Compounds 1 and 9 showed the highest enthalpy of binding to BET BD2, with a comparable entropic contribution to steric interactions.
Similarly, the imidazolyl and hydroxyl groups of compound 2 form strong, direct hydrogen bonds with conserved amino group residues on the CaBdf1 BD2. These interactions are distinct from those observed in the crystal structures of human Brd4 BD1 bound to JQ1, IBET-762 or PFI-1 (PDB codes 3MXF, 3P5O and 4C7N, respectively) where a water-mediated interaction is formed with a Tyr-425 sidechain (Supplementary Fig. 3d).
We further analyzed the structural basis for the BD2 selectivity of 1 using molecular modeling and docking simulations. The results indicated that the BD2-selectivity of the compound was due to a combination of hydrogen bonding with the phenolic ring and a partial positive charge on the Asn468 residue, whereas the BD1-selectivity resulted from a strong interaction between the phenolic ring and the WPF shelf (Supplementary Fig. 7d). The results suggest that the BD2-selectivity and cellular activity of 1 could be improved by a substitution in the phenolic ring to a less polar moiety, thereby reducing the positive charge contributions to steric interaction. Moreover, the BD2-selectivity of 2 could be enhanced by a change in the hydroxyl group to a more polar benzyl. This modification would allow the hydroxyl to interact with backbone atoms of the WPF shelf more directly, further stabilizing the BD2-binding interface and enhancing enthalpy of binding.
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