Cytokinetics’ contractility franchise has broad applicability over a number of therapeutic areas, including but not limited to heart failure, hypertension, frailty and asthma. Cytokinetics’ initial activities in this franchise area have been focused towards treatments for heart failure. Our expertise is built on an understanding of two key cytoskeletal proteins,
myosin and actin. Cardiac myosin is the cytoskeletal protein in the cardiac cell that is directly responsible for converting chemical energy through the hydrolysis of
ATP into the mechanical force that results in contraction. Cardiac muscle cell contractility is driven by the cardiac
sarcomere, the fundamental unit of muscle contraction in the heart that is a highly ordered cytoskeletal structure composed of cardiac myosin, actin and a set of regulatory proteins. The sarcomere represents one of the most thoroughly characterized protein machines in human biology. Cytokinetics advanced its first drug candidate from this franchise biology, CK-1827452, into the clinic in September 2005 for the potential treatment of acute heart failure. CK-1827452 is now the subject of an extensive Phase II clinical trials program.
Cytokinetics’ activities in the franchise biology area of cell cycle control, have been focused primarily towards disrupting mitotic function in cancer cells, but also encompass modulation of any activities in the normal cell cycle. To date, our drug discovery and development activities have been directed to the multi-protein systems involved in mitosis, namely the mitotic spindle, and key motor proteins, called mitotic kinesins. The mitotic spindle encompasses many cytoskeletal proteins including tubulin, which forms microtubule filaments, and a sub-group of kinesins known as mitotic kinesins. The highly orchestrated action of the proteins within this structure transports and segregates genetic material during cell proliferation.
Unlike current anti-mitotic agents that target tubulin and thus disrupt microtubule function, Cytokinetics’ drug candidates target two well characterized mitotic kinesins, kinesin spindle protein (KSP) and centrosome-associated protein E (CENP-E). KSP is a mitotic kinesin that functions exclusively in the initial steps of mitosis. The only known role of KSP is to separate spindle poles during prophase of mitosis. Cytokinetics’ expertise in cell cycle control has resulted in two drug candidates, ispinesib, now in Phase II clinical trials, and SB-743921, now in a Phase I/II clinical trial. Both drug candidates target and inhibit KSP function.
CENP-E is directly involved in coupling the mechanics of mitosis with the mitotic checkpoint signaling machinery, regulating cell-cycle transition from metaphase to anaphase. CENP-E is also essential for prometaphase chromosome movements that contribute to metaphase chromosome alignment. These processes are essential to cell proliferation. Cytokinetics’ expertise has also resulted in a drug candidate, GSK-923295, that specifically inhibits CENP-E and which exhibits properties that distinguish it from ispinesib and SB-743921.
Both franchise areas are driven by the company’s expertise in cytoskeletal biology and molecular motors, and leverage our cell biology driven discovery approach. Each are focused towards novel targets with the goal of developing next-generation drug candidates that are first-in-class.
