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Development of a Novel Multi-Isoform ALDH Inhibitor Effective As an Antimelanoma Agent Saketh S

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Development of a Novel Multi-Isoform ALDH Inhibitor Effective As an Antimelanoma Agent Saketh S Published OnlineFirst November 21, 2019; DOI: 10.1158/1535-7163.MCT-19-0360 MOLECULAR CANCER THERAPEUTICS | SMALL MOLECULE THERAPEUTICS Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent Saketh S. Dinavahi1,2,3, Raghavendra Gowda1,2,3,4, Krishne Gowda1, Christopher G. Bazewicz2,3,5, Venkat R. Chirasani1, Madhu Babu Battu6, Arthur Berg7, Nikolay V. Dokholyan1,8, Shantu Amin1, and Gavin P. Robertson1,2,3,4,5,9,10 ABSTRACT ◥ The aldehyde dehydrogenases (ALDH) are a major family of KS100 was mitigated by development of a nanoliposomal formu- detoxifying enzymes that contribute to cancer progression and lation, called NanoKS100. NanoKS100 had a loading efficiency of therapy resistance. ALDH overexpression is associated with a poor approximately 69% and was stable long-term. NanoKS100 was prognosis in many cancer types. The use of multi-ALDH isoform or 5-fold more selective for killing melanoma cells compared with isoform-specific ALDH inhibitors as anticancer agents is currently normal human fibroblasts. NanoKS100 administered intravenously hindered by the lack of viable candidates. Most multi-ALDH at a submaximal dose (3-fold lower) was effective at inhibiting isoform inhibitors lack bioavailability and are nonspecific or toxic, xenografted melanoma tumor growth by approximately 65% with- whereas most isoform-specific inhibitors are not effective as mono- out organ-related toxicity. Mechanistically, inhibition by KS100 therapy due to the overlapping functions of ALDH family members. significantly reduced total cellular ALDH activity to increase reac- The present study details the development of a novel, potent, multi- tive oxygen species generation, lipid peroxidation, and accumula- isoform ALDH inhibitor, called KS100. The rationale for drug tion of toxic aldehydes leading to apoptosis and autophagy. Col- development was that inhibition of multiple ALDH isoforms might lectively, these data suggest the successful preclinical development be more efficacious for cancer compared with isoform-specific of a nontoxic, bioavailable, nanoliposomal formulation containing a inhibition. Enzymatic IC50s of KS100 were 207, 1,410, and 240 novel multi-ALDH isoform inhibitor effective in the treatment of nmol/L toward ALDH1A1, 2, and 3A1, respectively. Toxicity of cancer. Introduction they often leave behind therapy-resistant cancer cells with a stem cell– like phenotype, which serve as a reservoir for disease recurrence and Malignant melanoma is an aggressive neoplasm accounting for the metastasis (3). majority of skin cancer–related deaths (1). The outlook for metastatic Cancer cells with stem cell characteristics comprise a small subset of disease remains poor, with current 5-year survival rates of 20% (1). undifferentiated cells that initiate tumor formation and generate However, treatment strategies for malignant melanoma have vastly multipotent progenitors (3). They promote tumor aggressiveness, improved with the discovery of targeted therapies to BRAF and MEK repopulation after injury, and metastasis, having intrinsic resistance along with the development of immune checkpoint inhibitors (2). to radiotherapy, chemotherapy, and targeted therapies (4). A major Although current treatment strategies may kill the bulk of tumor cells, mechanism by which these cells develop resistance is through upre- gulation of the aldehyde dehydrogenases (ALDH), which has impaired the response to preoperative chemotherapy and radiotherapy in 1Department of Pharmacology, The Pennsylvania State University College of esophageal carcinoma (5), conventional chemotherapy, erlotinib and Medicine, Hershey, Pennsylvania. 2The Melanoma and Skin Cancer Center, The gefitinib in lung carcinoma (6), olaparib in breast carcinoma (7), and Pennsylvania State University College of Medicine, Hershey, Pennsylvania. 3The cyclophosphamide in a myriad of carcinomas (8, 9). Melanoma Therapeutics Program, The Pennsylvania State University College of The 19 human ALDH isozymes are broadly defined as a superfamily 4 þ Medicine, Hershey, Pennsylvania. Foreman Foundation for Melanoma Research, of NAD(P) -dependent enzymes that participate in aldehyde metab- The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. 5Department of Dermatology, The Pennsylvania State University College of olism, catalyzing the oxidation of toxic aldehydes into carboxylic Medicine, Hershey, Pennsylvania. 6Laboratory of Molecular Cell Biology, Centre acids (10–13). ALDH activity within cells is generally a composite of for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad, India. 7Department the activities of multiple ALDH isoforms, which have overlapping of Public Health Sciences, The Pennsylvania State University College of Medicine, substrate specificity (14, 15). The ALDHs confer a survival advantage 8 Hershey, Pennsylvania. Department of Biochemistry and Molecular Biology, to metabolically active cancer cells, by oxidizing aldehydes that The Pennsylvania State University College of Medicine, Hershey, Pennsylvania. accumulate and cause oxidative damage, into less toxic, more soluble 9Department of Pathology, The Pennsylvania State University College of Med- icine, Hershey, Pennsylvania. 10Department of Surgery, The Pennsylvania State carboxylic acids (16, 17). Accordingly, ALDH overexpression is linked University College of Medicine, Hershey, Pennsylvania. to poorer survival in gastric, breast, lung, pancreatic, and prostate carcinomas, as well as in head and neck squamous cell carcinomas Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). (HNSCC; refs. 8, 11, 14, 18, 19). The ALDH1A1, 1A2, 1A3, 3A1, and 3A2 isozymes are particularly important in cancer progression and Corresponding Author: Gavin P. Robertson, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033. Phone: 717-531- resistance to anticancer therapies (8, 15, 20, 21). 8098; Fax: 717-531-0480; E-mail: [email protected] Current ALDH inhibitors can be categorized into multi-ALDH isoform inhibitors and isoform-specific inhibitors, which primarily Mol Cancer Ther 2020;19:447–59 inhibit one isoform (11). Limitations of multi-ALDH isoform inhi- doi: 10.1158/1535-7163.MCT-19-0360 bitors, such as N,N-diethylaminobenzaldehyde (DEAB), which targets Ó2019 American Association for Cancer Research. ALDH1A1, 1A2, 1A3, 1B1, 2, and 5A1, 4-dimethylamino-4-methyl– AACRJournals.org | 447 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst November 21, 2019; DOI: 10.1158/1535-7163.MCT-19-0360 Dinavahi et al. pent-2-ynthioic acid-S-methylester (DIMATE), which targets purchased from Tocris Biosciences. Isatin and the multi-ALDH ALDH1A1 and 3A1, and citral, which targets ALDH1A1, 1A3, and isoform inhibitor DEAB were purchased from Sigma Aldrich. 2, lack bioavailability or have toxicity (11). DIMATE has tumor- inhibitory efficacy when injected i.p. but will require further preclinical ALDH structure preparation evaluation (22). More recently, the ALDH inhibitors (aldis) -1, -2, -3, The structures of ALDH1A1, 2, and 3A1 bound to the inhibitors -4, and -6 have been developed, which target ALDH1A1, 2, and 3A1, CM037, psoralen, and CB7, respectively (4X4L, 5L13, and 4L2O), were and show efficacy in killing cultured cancer cells, particularly as retrieved from the protein data bank (PDB). The three-dimensional combinatorial therapy (23–25). However, these compounds have structures of the protein complexes were prepared using the protein mainly been tested in vitro and thus require further validation in preparation wizard tool (Schrodinger, LLC, 2017); water molecules preclinical models (23–25). were deleted except those in the inhibitor-binding pocket, bond orders Isoform-specific inhibitors, such as Cpd 3 and CM037 (targeting were assigned, hydrogen atoms were added, and metal ions were ALDH1A1), CVT10216 (targeting ALDH2), and CB7 and CB29 treated as described previously (35–37). Next, the orientation of the (targeting ALDH3A1), have limited efficacy in killing cultured cancer side chain structures of Gln and Asn was flipped, if necessary, to cells, particularly when used as monotherapy, and have not been tested provide the maximum degree of H-bond interactions. The charge state in animal cancer models (18, 26, 27). NCT-501, which targets of His residues was optimized. Finally, a restrained minimization of the ALDH1A1, has been shown to be effective in inhibiting HNSCC protein structure was performed using the OPLS force field with growth in animals via intratumoral injection, suggesting poor systemic backbone atoms being fixed. The minimized protein was used for the bioavailability (28). Other more bioavailable ALDH1A1-specific inhi- docking analysis. The structure was validated using Gaia webserver bitors have been developed, such as the orally bioavailable compounds (http://chiron.dokhlab.org). NCT-505 and NCT-506, and the i.p. available compounds 13 g and 13 h, but have not yet been evaluated in preclinical animal models (29, 30). ALDH grid generation and ligand preparation Therefore, ALDH inhibitors are needed that inhibit the multiple, Prepared protein structures were used to generate scoring grids for functionally overlapping ALDH isoforms, with an acceptable phar- subsequent docking calculations as described previously (35–37). To macologic profile. each protein crystal structure, a grid box of default size (20 Â 20 Â The current
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