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GX15-070 (obatoclax)
Status Obatoclax (GX15-070) is a small molecule indole bipyrrole drug compound that was discovered and is being developed at Gemin X. The attractive safety profile and mechanism of action of obatoclax offers the opportunity to treat many forms of cancer as both a single agent and in combination with current treatments. Obatoclax is currently being assessed in multiple Phase 1 and Phase 2 company-sponsored and National Cancer Institute (NIH) clinical trials directed against multiple solid tumor and hematologic malignancies. In addition to clinical activity in multiple indications, obatoclax is generally well tolerated, and is without evidence of immuno- and myelosuppression. Potential for combination therapeutic treatments- The promise and future of treatments in oncology will be the ability to rationally combine therapeutics that target the key regulators and pathways that collectively cause malignancies. Examples include separate pathways that together regulate the growth or survival of cancer cells. Other examples include resistance mechanisms. For example, the proteasome antagonist bortezomib (Velcade®) causes induction of the pro-survival Bcl-2 family member Mcl-1; combining Velcade with the pan Bcl-2 antagonist, obatoclax, which potently inhibits Mcl-1, results in strong combination synergies of these two agents in vitro in mantle cell lymphoma [1]. A similar result was recorded in multiple myeloma [2]. 2nd generation product- Obatoclax is currently administered by intravenous infusions on flexible schedules. To further optimize the treatment opportunities with obatoclax, a bolus intravenous and an oral formulation of the drug are under development. Mechanism of Action Obatoclax is a pan-inhibitor of the pro-survival members of the Bcl-2 family of apoptosis regulators. Many of the cellular events that initiate malignant transformation of a normal cell (e.g., activation of oncogenes) also activate oncogenic stress pathways that usually cause the cell to self destruct by a process called apoptosis [3]. In order for these cells to survive and cause cancer, they typically must have acquired changes in other cellular pathways to prevent apoptosis. The Bcl-2 family of proteins are important regulators and executioners of the cellular decision to live or die. Moreover, this family of proteins also dictates whether or not many current cancer therapies are effective, because most of these treatments result in stress signals that ultimately must activate the cancer cell’s apoptosis machinery. The Bcl-2 family is comprised of three groups of protein. One group protects against apoptosis and is comprised of five different proteins: Bcl-2 itself, Mcl-1, Bcl-XL, Bcl-w, and A1. The second group of proteins is represented by Bax and Bak. Although structurally very similar to the pro-survival members, Bax and Bak are the main activators of the apoptosis machinery in response to cellular stress stimuli. The third group is comprised of a heterogeneous group of proteins – the “BH3-only proteins” – and include such members as Bid, Bim, Puma, Bik, Bad, and others. The BH3-only proteins act to couple upstream cellular stress stimuli to responses by Bcl-2 pro-survival proteins and Bax, Bak death proteins. How these three groups integrate cell signaling into the decision to live or die is not completely understood and the mechanism remains controversial. However, key elements have been elucidated, which have uncovered a way to therapeutically modulate their behavior. Inhibiting pro-survival members is thought to allow oncogenic cell stress stimuli or stress stimuli resulting from other therapies, to drive the cancer cell into apoptosis. It is known, for example, that pro-survival members can bind pro-death members through the docking of the BH3 domain of death members into a deep groove on the surface of survival members (Fig. 1). If the pro-survival members are in excess in the cell, the pro-death members cannot trigger apoptosis due to these protein-protein interactions. Small molecule drugs that fit into the groove of the pro-survival members can prevent these protein-protein interactions, and re-instate the ability of the cell to self-destruct in response to stress stimuli. Increased expression of pro-survival members is a hallmark of many cancers, and drugs that can prevent their action are highly sought after. Figure 1: Restoring Natural Apoptosis with a Small Molecule 
The ability of pro-survival Bcl-2 members to block apoptosis requires that they interact with and inhibit the activation of Bax and Bak [4]. A major challenge in designing drugs that effectively prevent interactions between pro-survival Bcl-2 members and pro-death members, however, is the fact that both the pro-survival members and the pro-death executioners, Bax and Bak, function within the hydrophobic membrane of the outer membrane of the mitochondrion. Activation of Bax and Bak otherwise stimulate the release of cytochrome c and other pro-apoptotic factors from the mitochondrion, resulting in the activation of caspases and induction of apoptosis. Moreover, recent studies have found that stress stimuli operating through a BH3-only protein can cause changes in the shape of Bcl-2 and Bax,Bak, forcing them to penetrate further into the membrane lipid bilayer and promoting their protein-protein interactions [4] (Fig. 2). Bcl-2, for example, has been found to selectively interact only with a semi-activated conformation of Bak, capping its transition to the fully activated form. Further complicating the picture is the fact that Bcl-2 family proteins also function at the membrane of the endoplasmic reticulum, where they regulate calcium homeostasis and release, ER stress, and autophagy. Obatoclax is a hydrophobic drug that concentrates in the membranes where Bcl-2 proteins reside and function. It is poorly soluble in most aqueous-based solvents that are classically employed to study the properties of soluble proteins. In this in situ membrane context, however, it has been shown to potently inhibit pro-survival interactions with pro-death effector (Fig. 3). Additional studies have determined that obatoclax is a "pan" Bcl-2 antagonist, inhibiting all five pro-survival members. Figure 2: Bcl-2 inhibits Bax or Bak by preventing its oligomerization 
Figure 3: Bcl-2 inhibits Bax or Bak by preventing its oligomerization 
REFERENCES 1. Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D. The BH3-mimetic GX15-070 synergizes with Bortezomib in Mantle Cell Lymphoma by enhancing Noxa-mediated activation of Bak. Blood. 2007 Jan 16; [Epub ahead of print] 2. Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Pre-clinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. 3. Danial NN, Korsmeyer SJ. Cell death: critical control points. 4. Youle RJ. Cell biology. Cellular demolition and the rules of engagement.
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