Research Projects

Multiple myeloma (MM) and mantle cell lymphoma (MCL) are two distinct yet aggressive B-cell-derived hematological malignancies that, despite differences in origin and pathology, share some overlapping therapeutic vulnerabilities. MM originates in the bone marrow from malignant plasma cells, whose uncontrolled proliferation disrupts normal hematopoiesis. This leads to complications such as bone lesions, anemia, renal impairment, immune suppression, and increased susceptibility to infections. In contrast, MCL arises from B-cells within lymphoid tissues and is characterized by the overexpression of cyclin D1, which drives malignant cell growth. Importantly, both malignancies have shown clinical responsiveness to proteasome inhibitors—drugs that disrupt protein degradation pathways essential for cancer cell survival, highlighting a common therapeutic target. There is a need for continued exploration of proteasome-targeted and combination therapies to overcome resistance and improve long-term patient outcomes The proteasome is a large, multisubunit protease complex that plays a central role in intracellular protein degradation and maintaining cellular protein homeostasis. It selectively degrades misfolded, damaged, or short-lived regulatory proteins, including signaling molecules, tumor suppressors, cell-cycle regulators, etc. Given its central role in protein turnover, the proteasome has become an attractive therapeutic target, particularly, in cancers like MM and MCL. The 26S proteasome is a barrel-shaped protein complex composed of a 20S core particle and one or two 19S regulatory particles. The 20S core consists of four stacked rings, two outer α-rings and two inner β-rings, forming a central catalytic chamber. The β-subunits possess chymotrypsin-like, trypsin-like, and caspase-like functions. The 19S regulatory particles cap at the ends of the core and are responsible for recognizing ubiquitinated substrates, unfolding them, and translocating them into the 20S core for degradation. The Schematic representation of protean degradation by 26S proteasome and its inhibition is shown Scheme 1. Natural products along with their synthetic derivative have played a vital role in drug discovery, serving as a rich source of bioactive molecules with diverse chemical structures and pharmacological activities. Syrbactins are a class of peptide-polyketide hybrid natural products. Syrbactions such as, syringolin A and glidobactin A known for their potent and selective inhibition of the proteasome. Though these inhibit the proteasome activity, their structural activity around the core macrocyclic structure has not been investigated due to its structural complexity. In this proposal, we sought to investigate and find out potent proteasome inhibitor through structure activity relationships of syringolin A and glidobactin A derived around the core macrocyclic ring.