Mark S. Cushman
Our research group is engaged in the design and synthesis of a variety of molecules that interact with specific enzymes and membrane-bound receptors. This effort involves the integration of basic concepts in organic reaction mechanisms, synthetic organic chemistry, structural biology, biochemistry, computational chemistry, and pharmacology. At the present time, potential anticancer agents and antibiotics are being designed, synthesized, and tested.
In the anticancer drug development area, team members are focusing on novel indenoisoquinoline inhibitors of topoisomerase I. Work in this area has led to the synthesis of indenoisoquinolines containing amine side chains that confer exceptional potency as topoisomerase I inhibitors and as cytotoxic agents in human cancer cell cultures. Two indenoisoquinoline topoisomerase I inhibitors (LMP400 and LMP776) synthesized by the Cushman group have entered phase I clinical trials for treatment of cancer patients at the National Cancer Institute, and definite plans are being formulated to commence phase II clinical trials. The results of these clinical trials have been very promising, with no "show stoppers" involving bad ADME properties, lack of effects on biomarkers, or severe toxicities. In fact, the shrinkage of lung nodules in one cancer patient with colon cancer metastasis that was unresponsive to an array of established anticancer drugs, including irinotecan, after only one course of treatment with LMP400, is very encouraging. Recent work on the indenoisoquinolines has focused on synthesizing dual inhibitors of topoisomerase I and tyrosyl-DNA phosphodiesterase I. Since topoisomerase I inhibitors cause DNA breaks and tyrosyl-DNA phosphodiesterase I is involved in repairing them, the dual inhibitors my act synergistically to produce very potent anticancer activity. Strategies are also being investigated that are intended to target indenoisoquinolines specifically to prostate cancer cells and not normal cells in order to minimize undesirable systemic toxicity and improve efficacy.
Aromatase inhibitors are widely used in the treatment of breast cancer. However, they have significant side effects, including reduction in bone density leading to increase incidence of fractures, severe musculoskeletal pain leading to reduced patient compliance, and increase frequency of cardiovascular events. These undesirable effects are thought to be due to global estrogen depletion directly resulting from inhibition of aromatase. Cushman's research group is presently synthesizing aromatase inhibitors that also bind to estrogen receptors in normal cells and are designed to produce estrogenic effects in non-tumor tissues. The overall goal of this project is to design and synthesize compounds that inhibit estrogen production, block estrogen receptors in breast cancer cells, and stimulate estrogen receptors in normal cells. This is expected to result in an anticancer drug that would effectively treat breast cancer while greatly improving the quality of the lives of patients undergoing breast cancer chemotherapy.
Cancer prevention obviously offers distinct advantages over cancer treatment. A number of receptors that are involved in carcinogenesis are therefore being targeted by the Cushman group, including quinone reductases 1 and 2, NFΚB, retinoid X receptor, inducible nitric oxide synthase, the estrogen receptor, cyclooxygenases 1 and 2, MAPKs (p38 and Jun N-terminal kinase), and p21.
D. E. Beck, W. Lv, M. Abdelmalak, C. B. Plescia, K. Agama, C. Marchand, Y. Pommier, and M. Cushman, "Synthesis and Biological Evaluation of new Fluorinated and Chlorinated Indenoisoquinoline Topoisomerase I Inhibitors," Bioorg. Med. Chem. 24, 1469-1479 (2016).
D. E. Beck, P. V. N. Reddy, W. Lv, M. Abdelmalak, G. S. Tender, S. Lopez, K. Agama, C. Marchand, Y. Pommier, and M. Cushman, "Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase I Poisons," J. Med. Chem. 59, 3840-3853 (2016).
P.-C Lv, M. S. A. Elsayed, K. Agama, C. Marchand, Yves Pommier, and M. Cushman, "Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400)," J. Med. Chem. 59, 4890-4899 (2016).
A. Hoshi, T. Sakamoto, J. Takayama, M. Xuan, M. Okazaki, T. Hartman, R. Buckheit Jr., C. Pannecouque, and M. Cushman, "Systematic Evaluation of Methyl Ester Bioisosteres in the Context of Developing Alkenyldiarylmethanes (ADAMs) as Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) for anti-HIV-1 Chemotherapy," Bioorg. Med. Chem. 24, 3006-3022 (2016).
L.-M. Zhao, H.-S. Jin, J. Liu, T. Skaar, J. Ipe, W. Lv, D. A. Flockhart, and M. Cushman "A New Suzuki Synthesis of Triphenylethylenes that Inhibit Aromatase and Bind to Estrogen Receptors a and b," Bioorg. Med. Chem. 24, 5400-5409 (2016).
M. S. A. Elsayed, M. Zeller, and M. Cushman "Synthesis of Indolo[4,3-bc]phenanthridine-6,11(2H,12H)-diones Using the Schiff Base–Homophthalic Anhydride Cyclization Reaction," Syn. Commun. 46, 1902-1908 (2016).
M. Haroon, W. Younis, L. Chen, C. E. Peters, J. Pogliano, K. Pogliano, B. Cooper, J. Zhang, A. Mayhoub, E. Oldfield, M. Cushman, and M. Seleem "Phenylthiazole Antibacterial Agents Targeting Cell Wall Synthesis Exhibit Potent Activity In Vitro and In Vivo against Vancomycin-resistant Enterococci," J. Med. Chem. 60, 2425-2438 (2017).
J.-C. Tian, X. Han, W. Lv, Y.-X. Li, H, Wang, B.-Z. Fan, M. Cushman, J.-H. Liang "Design, Synthesis, and Structure-Bactericidal Activity Relationships of Novel 9-Oxime Ketolides and Reductive Epimers of Acylides", Bioorg. Med. Chem. Lett. 27, 1513-1524 (2017).
P. Wang, M. S. A. Elsayed, C. B. Plescia, A. Ravji, C. E. Redon, E. Kiselev, C. Marchand, O. Zeleznik, K. Agama, Y. Pommier, and M Cushman "Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl−DNA Phosphodiesterase 1 (Tdp1), and Tyrosyl−DNA Phosphodiesterase 2 (Tdp2)," J. Med. Chem. 60, 3275-3288 (2017).
J. H. Liang, L. Yang, S. Wu, S.-S. Liu, M. Cushman, J. Tian, N.-M. Li, Q.-H. Yang, H.-O. Zhang, Y.-J. Qui, L. Xiang, C.-X. Ma, X.-M. Li, and H. Qing "Discovery of Efficient Stimulators for Adult Hippocampal Neurogenesis Based on Scaffolds in Dragon's Blood," Eur. J. Med. Chem. 136, 382-392 (2017).