While the binding of HK to

While the binding of HK1 to VDAC1 is strong and continuous, the binding of HK2 to VDAC1 is much weaker, and alternates between a cytoplasmic and a mitochondrial-bound states (John et al., 2011). This dynamic process is regulated by the metabolic and energetic requirements of the enos inhibitor and provides them with significant advantages. First, VDAC1-bound HK2 protects cells from apoptosis, thus enabling their longevity (Gottlob et al., 2001, Majewski et al., 2004, Pastorino et al., 2002). Second, by binding to VDAC1, HK2 gains privileged access to ATP synthesized in the mitochondria, its preferred source for substrate utilization (Pastorino and Hoek, 2008, Wilson, 2003). Finally, this association results in reduced sensitivity to feedback inhibition by the glucose-6-phosphate product (John et al., 2011, Wilson, 2003). Taken together, the selective dissociation of HK2 from VDAC1 should trigger apoptosis in cancer cells, making it a promising anti-cancer strategy (Krasnov et al., 2013). HK2 has been proposed as a potential target for anti-cancer therapy and a few HK2 inhibitors were recently published (Krasnov et al., 2013, Li et al., 2017a, Li et al., 2017b, Lin et al., 2016). Here we present a selective small molecule modulator of HK2’s interaction with the mitochondria (Comp-1, Figure 1), which is a highly potent synthetic derivative of methyl jasmonate, a well-documented plant stress hormone with some reported anti-cancer activity (Goldin et al., 2008, Krasnov et al., 2013). Comp-1 does not affect the binding of the normal isoform, HK1, to the mitochondria, thus, representing a potentially well-tolerated anti-cancer drug for AK and cutaneous SCC, as well as for other tumor types.
Results
Discussion We present here a targeted approach to treat cancer with an allosteric modulator that selectively detaches HK2 from the mitochondria, without affecting HK1 association, resulting in glycolysis reduction and induction of apoptosis in the malignant cells. Comp-1’s anti-proliferative effect in vitro is correlated with HK2 protein levels in the cells. Specifically, Comp-1 exhibits broad anti-cancer activity in vitro as well as in vivo efficacy in the UVB-damaged skin mouse model. The in vivo efficacy of Comp-1 (70% reduction in lesion count) is similar to the reported efficacy of ingenol mebutate in a similar mouse model (Cozzi et al., 2012). Pharmacodynamic analysis of HK isoform levels in the skin of treated mice confirms Comp-1’s selective mode of action: reducing the high HK2 levels characteristic of the disease state to low HK2 levels similar to those in normal skin. This effect was demonstrated as early as 2 days after initiation of treatment. Unlike most other approved AK drugs that cause significant skin irritation, the efficacy of Comp-1 is delivered without irritation. Good Laboratory Practice toxicology studies in minipigs with a topical ointment formulation of Comp-1 administered once daily for 28 days and 13 weeks established no systemic toxicities and minimal dermal reaction for doses of up to 20% and 15%, respectively. Tolerability for topical AK treatments is a major consideration in the management of this disease. Due to field cancerization that is brought about by prolonged exposure to the sun, AK patients require repeat treatments during their lifetime, often over large areas of skin. Lesion-directed treatments, such as cryosurgery and laser-based therapies, are not suitable for treatment of multiple lesions over large areas. Current efficacious field-directed treatments (including 5-fluorouracil, imiquimod, ingenol mebutate, and photodynamic treatment) are frequently associated with severe local skin reactions, which range from moderate inflammation to necrosis. These reactions are painful and unsightly, leading to reduced treatment compliance. Comp-1, which demonstrates efficacy, safety, and dermal tolerability in vivo, may address a significant unmet medical need for subjects with AK. Comp-1 is in clinical developed as a topical treatment for AK, currently in a phase 2b trial. It is also being developed as a systemic treatment for other malignant diseases.