Current Chemical Biology - Volume 8, Issue 3, 2014

Duchenne Muscular Dystrophy (DMD) is one the most frequent genetic disorder that affects 1 in every 3500 males worldwide. This fatal neuromuscular disorder arises from the defects in the protein, called dystrophin. The dystrophin coding gene is the largest known gene and present in X chromosome. Several strategies, ranging from cell based therapy to small RNA mediated exon skipping have been proposed as an effective therapy for this disease. Experiments in mice model have shown that upregulation of utrophin, the autosomal homologue of dystrophin can compensate dystrophin deficiency and ameliorate the dystrophic phenotype. Therefore utrophin has also been considered as a potent target for development of strategies against DMD. In the current review we describe different therapeutic approaches for DMD along with challenges they have to overcome.

Activated hedgehog signaling (Hh) cascade was first found in basal cell carcinoma but with time it has been found in other major cancer types including medulloblastoma (MB), pancreatic cancer, small cell lung cancer, liver cancer, leukemia etc. Small molecule antagonists of Hh pathway were developed to block either Hh ligands or Smoothened (Smo), a transmembrane receptor that controls Gli based downstream signaling cascades of Hh pathway. Among many Smo inhibitors like naturally occurring cyclopamine or synthetic small molecule IPI-926, GDC-0449, LDE-225, GANTs etc few small molecules are in clinical trial, and one small molecule GDC-0449 has been approved by FDA. Limitation of using Smo antagonists is due to rapid mutation in Smo itself and hence the new generation Hh antogonists like HPI-1 or HPI-2 have been developed which are capable of bypassing Smo and attacking downstream effector Gli1 directly and hence the major activated Hh pathway effectors or entire Hh signaling are suppressed. In this review, we will discuss the development of different small molecule inhibitors of Hh pathway to treat cancer.

Proteins are always at risk inside the cellular environment. Stress enhances the propensity of protein misfolding. Cell has evolved dynamic machinery called protein quality control (PQC) to minimize the risk of protein misfolding. The efficiency of PQC decreases during ageing; and the tendency of misfolded protein accumulation reduces the lifespan of an organism. Cell reduces the flux of misfolded proteins by refolding, degradation, or by sequestering into inclusions. Several evidences support the involvement of molecular chaperones that act as primary cellular defense. Among these, Hsp70 protein plays the prime function in maintaining PQC. Hsp70 has the unique ability to attune its function in response to the cellular need. From folding to degradation, solubilising aggregates, refolding of damaged proteins, and preventing harmful assemblage of protein inclusions, Hsp70 portrays a wide array of functions. These functions are attributed by the chaperone alone or along with its co-chaperones, Hsp40 (J-proteins), Hsp110 (NEF’s) or Hsp104. Recent studies indicate Hsp70 as a degradation chaperone that efficiently facilitates in clearance of misfolded proteins. We discuss here the diverse roles of Heat Shock Protein 70 (Hsp70) chaperone in client fate determination. Moreover, we focus on the strategies cell undertake when major chaperone functions are compromised due to targeted inhibition or particular stress conditions. In the light of these findings, we discuss how chaperone modulation can evolve as an effective strategy to combat various neuropathies, ion channel misfolding diseases and selective parasitic maladies.

Tubulin-Microtubule (MT) system has long been implicated in multiple crucial cellular functions like cell division, maintenance of cell shape and structure, intracellular transport and propagation of signal transduction. This complex entity composed of αβ tubulin heterodimer can account for mitotic arrest followed by induction of cell suicide event due to its dynamic character. Being a target for a number of natural as well as synthetic small molecules blocking cell cycle progression has made tubulin-MT system an effective subject of research. This drive to combat proliferation of cancerous cell growth is still continuing with the advent of small molecule inhibitors. These antitubulin agents can be divided into two flavors; promoting assembly of tubulin to stable MT and inhibiting polymerization of αβ tubulin to MT polymer. But in most of the cases an additional subtle mechanism known as microtubule dynamics (catastrophe or treadmilling and rescue) has been attenuated by small molecule inhibitors imposing an impasse to the progress of cell cycle. Colchicine is the ancient antitubulin drug inhibiting polymerization but cannot be utilized with full potential due to its necrotoxic behavior. That is why colchicine site inhibitors (CSI) have been designed, synthesized and tested in order to get potential antimitotic agents of future promise. In this review, an effort has been initiated to unravel the mechanistic approach using MTs as anticancer drug target focusing colchicine binding site. Along with the history of development of CSIs, a modern update of recently explored colchicine site targeting agents has been discussed with a prelude of MT dynamics, role of microtubule associated proteins (MAPs) affecting MT stability and with a vivid description of factors conferring resistance to antimitotic agents.

Matrix metalloproteinases (MMPs) are family zinc containing calcium dependent enzymes. They can degrade the different components of extracellular matrixin normal as well as in abnormal condition. MMPs have been found in vertebrates, invertebrates and plants. The synthesis, translocation and function of MMPs are mostly associated with different signaling cascades. The functions of MMPs are intricately regulated by its specific endogenous regulators or the inhibitors known as tissue inhibitor of metalloproteinases (TIMPs) in the time of activation and in inhibition. MMPs and TIMPs are involved in the regulation of cell characteristics in normal as well as the state of human morbidity and mortality. There are numerous roles of MMPsin normal physiological processes and that are good. Again, the ugly is the abnormal activity or overexpression of MMPs that has the distinct role in many disease processes. Presently, broad-spectrum synthetic as well as natural MMP inhibitors have been developed or isolated for the treatment of manyfatal diseases and also sometime for managing the critical complications there in. Therefore, the diverse role of all the MMPs and TIMPs cannot be explained precisely in a particular review because of their multidirectional and multifunctional behavior in mammals. This review is a very small effort to delineate some of the progresses not all in a precise manner with an elaborative description of MMPs towards their multifaceted functions in the light of human physiology and pathology concerned.