{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:32:14Z","timestamp":1785407534859,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Center","award":["UMO-2021\/43\/B\/NZ7\/01732"],"award-info":[{"award-number":["UMO-2021\/43\/B\/NZ7\/01732"]}]},{"award":["UMO-2021\/43\/B\/NZ7\/01732"],"award-info":[{"award-number":["UMO-2021\/43\/B\/NZ7\/01732"]}],"id":[{"id":"https:\/\/ror.org\/03ha2q922","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Castration-resistant prostate cancer (CRPC) remains a significant clinical challenge due to the ability of tumor cells to undergo intratumoral androgen synthesis, a process catalyzed by the CYP17A1 enzyme. The only CYP17A1 inhibitor available in therapy, abiraterone acetate, faces significant limitations due to its steroidal structure, which causes off-target effects and generates agonistic metabolites that paradoxically stimulate the androgen receptor (AR). This study presents the development of the D2AAK1M series, a novel class of non-steroidal potential CYP17A1 inhibitors based on a pyridine\u2013piperidine scaffold. Through biomimetic design and molecular docking, we demonstrated that these compounds have the potential to coordinate the heme iron while achieving high shape complementarity within the catalytic pocket. In silico ADME profiling indicated superior physicochemical properties compared to abiraterone, including optimal lipophilicity, enhanced water solubility, and the potential to penetrate the blood\u2013brain barrier for targeting CNS metastases. In vitro assay results correlated with a suggested mechanism, showing preferential cytotoxicity toward androgen-dependent LNCaP cells (AR+) while sparing AR-negative lines (DU145, PC3) and healthy human fibroblasts (BJ). Our compounds present a promising starting point for further development of non-steroidal CYP17A1 inhibitors.<\/jats:p>","DOI":"10.3390\/molecules31122135","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T10:19:53Z","timestamp":1781691593000},"page":"2135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis, Molecular Modeling and Assessment of Anticancer Activity of New Potential CYP17A1 Inhibitors"],"prefix":"10.3390","volume":"31","author":[{"given":"Micha\u0142 K.","family":"Jastrz\u0119bski","sequence":"first","affiliation":[{"name":"Doctoral School, Medical University of Lublin, 20-093 Lublin, Poland"},{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chod\u017aki St., 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2027-9681","authenticated-orcid":false,"given":"Agnieszka","family":"Korga-Plewko","sequence":"additional","affiliation":[{"name":"Independent Medical Biology Unit, Medical University of Lublin, 8b Jaczewski St., 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Iwan","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Faculty of Pharmacy, Medical University of Lublin, 8b Jaczewski St., 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2766-3870","authenticated-orcid":false,"given":"Joanna","family":"Kubik","sequence":"additional","affiliation":[{"name":"Doctoral School, Medical University of Lublin, 20-093 Lublin, Poland"},{"name":"Independent Medical Biology Unit, Medical University of Lublin, 8b Jaczewski St., 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Stachniuk","sequence":"additional","affiliation":[{"name":"Department of Bioanalytics, Faculty of Medical Sciences, Medical University of Lublin, 8b Jaczewski St., 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Fornal","sequence":"additional","affiliation":[{"name":"Department of Bioanalytics, Faculty of Medical Sciences, Medical University of Lublin, 8b Jaczewski St., 20-090 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0313-2522","authenticated-orcid":false,"given":"Tomasz M.","family":"Wr\u00f3bel","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chod\u017aki St., 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka A.","family":"Kaczor","sequence":"additional","affiliation":[{"name":"Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of Lublin, 4A Chod\u017aki St., 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"e70043","article-title":"Cancer Statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/aps.2014.18","article-title":"Androgen Receptor: Structure, Role in Prostate Cancer and Drug Discovery","volume":"36","author":"Tan","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.20892\/j.issn.2095-3941.2024.0139","article-title":"Luteinizing Hormone-Releasing Hormone Receptor Agonists and Antagonists in Prostate Cancer: Effects on Long-Term Survival and Combined Therapy with next-Generation Hormonal Agents","volume":"21","author":"Zhao","year":"2024","journal-title":"Cancer Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.eururo.2014.09.049","article-title":"Understanding the Mechanisms of Androgen Deprivation Resistance in Prostate Cancer at the Molecular Level","volume":"67","author":"Karantanos","year":"2015","journal-title":"Eur. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1158\/0008-5472.CAN-08-0249","article-title":"Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth","volume":"68","author":"Montgomery","year":"2008","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6542","DOI":"10.1021\/acs.jmedchem.3c00442","article-title":"Non-Steroidal CYP17A1 Inhibitors: Discovery and Assessment","volume":"66","author":"Pandey","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"596","DOI":"10.7150\/ijbs.8780","article-title":"Roles for the Backdoor Pathway of Androgen Metabolism in Prostate Cancer Response to Castration and Drug Treatment","volume":"10","author":"Fiandalo","year":"2014","journal-title":"Int. J. Biol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"83","DOI":"10.6065\/apem.2244124.062","article-title":"Classic and Backdoor Pathways of Androgen Biosynthesis in Human Sexual Development","volume":"27","author":"Lee","year":"2022","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.2147\/DDDT.S15850","article-title":"Abiraterone Acetate: Oral Androgen Biosynthesis Inhibitor for Treatment of Castration-Resistant Prostate Cancer","volume":"6","author":"Rehman","year":"2012","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102999","DOI":"10.1016\/j.jbc.2023.102999","article-title":"Human Cytochrome P450 17A1 Structures with Metabolites of Prostate Cancer Drug Abiraterone Reveal Substrate-Binding Plasticity and a Second Binding Site","volume":"299","author":"Petrunak","year":"2023","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.jsbmb.2016.04.021","article-title":"The Hunt for a Selective 17,20 Lyase Inhibitor; Learning Lessons from Nature","volume":"163","author":"Bird","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1158\/1078-0432.CCR-12-0931","article-title":"Molecular Pathways: Inhibiting Steroid Biosynthesis in Prostate Cancer","volume":"19","author":"Ferraldeschi","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2463014","DOI":"10.1080\/14756366.2025.2463014","article-title":"Pyridine Indole Hybrids as Novel Potent CYP17A1 Inhibitors","volume":"40","author":"Yakubu","year":"2025","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"S529","DOI":"10.21037\/tcr.2016.07.35","article-title":"Directing Abiraterone Metabolism: Balancing the Scales between Clinical Relevance and Experimental Observation","volume":"5","author":"Obst","year":"2016","journal-title":"Transl. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature17954","article-title":"Redirecting Abiraterone Metabolism to Fine-Tune Prostate Cancer Anti-Androgen Therapy","volume":"533","author":"Li","year":"2016","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.2147\/DDDT.S93941","article-title":"Galeterone for the Treatment of Advanced Prostate Cancer: The Evidence to Date","volume":"10","author":"Bastos","year":"2016","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"803","DOI":"10.2217\/fon.14.35","article-title":"Orteronel for the Treatment of Prostate Cancer","volume":"10","author":"Huang","year":"2014","journal-title":"Future Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1200\/JCO.2014.56.5119","article-title":"Phase III, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) plus Prednisone with Placebo plus Prednisone in Patients with Metastatic Castration-Resistant Prostate Cancer That Has Progressed during or after Docetaxel-Based Therapy: ELM-PC 5","volume":"33","author":"Fizazi","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/S0022-5347(05)64675-7","article-title":"Low Dose Ketoconazole With Replacement Doses of Hydrocortisone in Patients With Progressive Androgen Independent Prostate Cancer","volume":"168","author":"Harris","year":"2002","journal-title":"J. Urol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1014618","article-title":"Abiraterone and Increased Survival in Metastatic Prostate Cancer","volume":"364","author":"Logothetis","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.clgc.2019.11.002","article-title":"Phase 2 Study of Seviteronel (INO-464) in Patients With Metastatic Castration-Resistant Prostate Cancer After Enzalutamide Treatment","volume":"18","author":"Madan","year":"2020","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_23","unstructured":"(2026, June 10). Janssen Marks First Approval Worldwide for AKEEGA\u00ae (Niraparib and Abiraterone Acetate Dual Action Tablet) with EC Authorisation for the Treatment of Patients with Metastatic Castration Resistant Prostate Cancer with BRCA1\/2 Mutation. Available online: https:\/\/s203.q4cdn.com\/636242992\/files\/doc_news\/2023\/04\/AKEEGA-Niraparib-and-Abiraterone-Acetate-Dual-Action-Tablet-approval-press-release-1.pdf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s40291-022-00594-2","article-title":"Lutetium Lu 177 Vipivotide Tetraxetan: First Approval","volume":"26","author":"Keam","year":"2022","journal-title":"Mol. Diagn. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103043","DOI":"10.1016\/j.japh.2026.103043","article-title":"Economic Evaluation of Talazoparib and Enzalutamide Compared to Enzalutamide Monotherapy in HRRm Metastatic Castration-Resistant Prostate Cancer","volume":"66","author":"Lukan","year":"2026","journal-title":"J. Am. Pharm. Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.neuint.2016.03.003","article-title":"In Vitro, Molecular Modeling and Behavioral Studies of 3-{[4-(5-Methoxy-1H-Indol-3-Yl)-1,2,3,6-Tetrahydropyridin-1-Yl]Methyl}-1,2-Dihydroquinolin-2-One (D2AAK1) as a Potential Antipsychotic","volume":"96","author":"Kaczor","year":"2016","journal-title":"Neurochem. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e70232","DOI":"10.1111\/jnc.70232","article-title":"Unveiling the Therapeutic Potential of D2AAK1 and Its Derivatives: Mechanistic Insights and Applications in Neurodegenerative Disease Treatment","volume":"169","author":"Mudgal","year":"2025","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Asim, A., Jastrz\u0119bski, M.K., and Kaczor, A.A. (2025). Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase-B for the Treatment of Alzheimer\u2019s Disease. Molecules, 30.","DOI":"10.3390\/molecules30142975"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1021\/ci000383k","article-title":"Robustness of Biological Activity Spectra Predicting by Computer Program PASS for Noncongeneric Sets of Chemical Compounds","volume":"40","author":"Poroikov","year":"2000","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nature10743","article-title":"Structures of Cytochrome P450 17A1 with Prostate Cancer Drugs Abiraterone and TOK-001","volume":"482","author":"DeVore","year":"2012","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Saranyutanon, S., Deshmukh, S.K., Dasgupta, S., Pai, S., Singh, S., and Singh, A.P. (2020). Cellular and Molecular Progression of Prostate Cancer: Models for Basic and Preclinical Research. Cancers, 12.","DOI":"10.3390\/cancers12092651"},{"key":"ref_32","first-page":"211","article-title":"Androgen Receptor Signalling in Prostate Cancer: Mechanisms of Resistance to Endocrine Therapies","volume":"17","author":"Quistini","year":"2025","journal-title":"Res. Rep. Urol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4946","DOI":"10.1021\/acs.jmedchem.8b00419","article-title":"Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2","volume":"61","author":"Fehl","year":"2018","journal-title":"J. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/12\/2135\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T10:20:43Z","timestamp":1781691643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/12\/2135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["molecules31122135"],"URL":"https:\/\/doi.org\/10.3390\/molecules31122135","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]}}}