Therapeutic Opportunities Offered by the Excessive Lactate Production in Cancer

The majority of cancers of various tissue origin display wide portions suffering from insufficient respiration, due to permanent or transient hypoxia, which occurs during tumor development. This condition leads to the development of a glycolytic phenotype, where a compensatory lactate production takes place, in order to provide the cancer cells with sufficient amounts of energy and anabolites. Lactate is not just as a waste product of the glycolytic process, instead it plays a key role in the progression of cancer, since it promotes angiogenesis, cell migration, immune escape and radioresistance. Moreover, lactate can still constitute a metabolic fuel for oxidative tumor cells or vascular endothelial cells, and it can establish a symbiotic cell-cell shuttling system with stromal cells. Therefore, these peculiar roles of lactate in invasive tumors constitutes a high-priority target for future anti-cancer therapeutics [1]. Therapeutic interventions aimed at reducing lactate production in cancer tissues may consist of: a) reduction of glucose uptake (calorie-restricted ketogenic diet, physical exercise, inhibitors of glucose transporters); b) inhibition of enzymes involved in key-steps of glycolysis (inhibitors of hexokinase, phosphofructokinase, lactate dehydrogenase); c) block of the cellular trafficking of lactate (inhibitors of monocarboxylate transporters); d) enhancement of the mitochondrial oxidative metabolism (hyperbaric oxygen therapy, removal of inhibition of the Krebs cycle, for example, by using inhibitors of pyruvate dehydrogenase kinase) [2]. We have developed compounds that exert an anti-proliferative action on cancer cells by specific interventions on cancer metabolism, such as, inhibition of lactate dehydrogenase (LDH) activity [3,4], or reduction of glucose uptake through specific transmembrane transporters (GLUT) [5]. Furthermore, some of the LDH-inhibitors demonstrated a remarkable synergism with gemcitabine against pancreatic cancer cells in hypoxia [6]. and an improved activation of the redox-sensitive anti-cancer prodrug EO9 by means of an induced increase of the NADH/NAD+ cell ratio [7]. It is important to note that the development of agents that target lactate production, trafficking, and metabolism (by these or other methods) hold promise for treating nearly all invasive cancers, provided they present an appropriate therapeutic window. References 1) J. R. Doherty, J. L. Cleveland. J. Clin. Invest. 2013, 123, 3685–3692. 2) C. Granchi, F. Minutolo. ChemMedChem 2012, 7, 1318-1350. 3) C. Granchi, S. Roy, C. Giacomelli, et al. J. Med. Chem. 2011, 54, 1599–1612. 4) E. C. Calvaresi, C. Granchi, T. Tuccinardi, et al. ChemBioChem 2013, 14, 2263–2267. 5) T. Tuccinardi, C. Granchi, J. Iegre, et al. Bioorg. Med. Chem. Lett. 2013, 23, 6923–6927. 6) M. Maftouh, A. Avan, R. Sciarrillo, et al. Br. J. Cancer 2014, 110, 172-182. 7) S. J. Allison, J. R. P. Knight, C. Granchi, et al. Oncogenesis 2014, 3, e102; DOI: 10.1038/oncsis.2014.16

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3‑3 Protein–Protein Interaction

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein–protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3‑3 Protein–Protein Interaction

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein–protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators

Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and (R)-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-μM IC50 against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays

Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and (R)-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-μM IC50 against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays

Design, Synthesis, and Evaluation of Inhibitors of Hedgehog Acyltransferase

Hedgehog signaling is involved in embryonic development and cancer growth. Functional activity of secreted Hedgehog signaling proteins is dependent on N-terminal palmitoylation, making the palmitoyl transferase Hedgehog acyltransferase (HHAT), a potential drug target and a series of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines have been identified as HHAT inhibitors. Based on structural data, we designed and synthesized 37 new analogues which we profiled alongside 13 previously reported analogues in enzymatic and cellular assays. Our results show that a central amide linkage, a secondary amine, and (R)-configuration at the 4-position of the core are three key factors for inhibitory potency. Several potent analogues with low- or sub-μM IC50 against purified HHAT also inhibit Sonic Hedgehog (SHH) palmitoylation in cells and suppress the SHH signaling pathway. This work identifies IMP-1575 as the most potent cell-active chemical probe for HHAT function, alongside an inactive control enantiomer, providing tool compounds for validation of HHAT as a target in cellular assays