- Undergraduate degree in chemistry/biochemistry at the Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, 10000 Croatia
- Master Degree in Biochemistry, at the Faculty of Biochemistry and Pharmacy, University of Zagreb, Zagreb, 10000 Croatia (mentors Jelena Momirovic-Culjat and Ruzica Henneberg)
- PhD degree in Bioinorganic Chemistry at the Faculty of Biochemistry and Pharmacy, University of Zagreb, Zagreb, 10000 Croatia (mentor – Mladen Birus)
- Postdoctoral studies at Department of Chemistry, Duke University (mentor - Alvin Crumbliss), and Department of Biochemistry, Duke University School of Medicine (mentor – Irwin Fridovich), Durham, NC 27707
- Citations – 14 084, h-Index 59
Presently, I hold the position of Professor Emeritus at the Department of Radiation Oncology, Duke University School of Medicine. I have over 40 years of research experience. More than half of my career my research has been centered on the field of redox biology and medicine and in particular on the design of SOD mimics for anticancer therapy and radioprotection; understanding of their mechanism of action was one of my major goals.
My Lab has worked on: (i) design, synthesis and characterization of different redox-active therapeutics, primarily Mn porphyrins; (iii) characterization of their aqueous chemistry with regards to the biologically relevant reactive species such as superoxide, peroxynitrite, hydrogen peroxide, ascorbate, simple and protein thiols and nitric oxide; (iii) bioavailability studies on Mn porphyrins in cells, tissues and cellular fragments, and (iv) cellular and animal experiments in support of mechanistic studies. To better understand redox-active therapeutics, we have routinely compared Mn porphyrins to other redox-active drugs developed towards clinical trials, such as Mn(II) cyclic polyamines, Mn(III) salens, Mn(II) salts and nitroxides.
Our success in drug design is best evidenced in establishing structure-activity relationship (SAR) for Mn porphyrins with regards to SOD mimicking; however the SAR is relevant to different other redox-active compounds. The SAR has led to the design and synthesis of several lead compounds, two of which are in 4 clinical trials - MnTE-2-PyP5+ (BMX-010, AEOL10113) and MnTnBuOE-2-PyP5+ (BMX-001). Three Phase I/II Clinical Trials are now in progress on testing BMX-001-driven radioprotection of normal brain with glioma patients (NCT02655601), radioprotection of salivary glands and mouth mucosa with head&neck (NCT02990468) and radioprotection of gastrointestinal and genitoourinary systems with anal cancer patients (NCT0338650). Trial on atopical dermatitis, psoriasis and itch is in progress on BMX-010 (NCT03381625). BMX-010 was used in trial on islet cells transplant; trial on BMX-001 on same application is in preparation. A diethylimidazolyl analog of MnTE-2-PyP5+, MnTDE-2-ImP5+ (AEOL10150), has been successfully used in Phase I trials on ALS patients.
The design and understanding of the actions of Mn porphyrins are greatly driven by the impressive results on the efficacy of Mn porphyrins which have been demonstrated in cellular and animal studies conducted by numerous colleagues - biochemists, biologists and medical professionals, within and outside of USA. Many groups at and outside of Duke University, such as those led by Spasojevic, Warner, Sheng, Dewhirst, Zennadi, Benov, St, Clair, Huang, Tome, Piganelli, Ferrari, Cobley, Oberley-Deegan, Coleman and Radi, have been involved in the development of Mn porphyrins. Support from different sources, such as NIH, DoD, Duke Translational Research Institute, Duke School of Medicine, Wallace H Coulter Foundation, NC Biotechnology Agency and BioMimetix JVLLC, has been highly appreciated.
The interdisciplinary approach has supplied us with enthusiasm and justification from in vitro and in vivo studies essential for the continuation of the drug development. On the other side, our insight into the chemistry of Mn porphyrins helped our colleagues adopt appropriate approaches in studying possible biologically relevant reactions of Mn porphyrins and pathways they impact, as well as discuss the effects they observe.
Work in my Lab resulted in 210 peer-reviewed manuscripts, 226 presentations and 5 book chapters, as well as numerous compositional and use patents and patent applications.