Mark S. Cushman
Ph.D. - 1973 - University of California Medical Center, San Francisco
Postdoc - 1973-75 - Massachusetts Institute of Technology
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.
S. A. Elsayed, J. J. Nielsen, S. Park, J. Park, Q Liu, C. H. Kim, Y. Pommier, K. Agama, P. S. Low, and M. Cushman, "Application of Sequential Palladium Catalysis for the Discovery of Janus Kinase Inhibitors in the Benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-5-one (BPN) Series," J. Med. Chem. 61, 10440-10462 (2018).
Pommier, M. Cushman, and J. H. Doroshow, "Novel Clinical Indenoisoquinoline Topoisomerase I Inhibitors: a Twist Around the Camptothecins," Oncotarget 9, 37386-37288 (2018).
C.-X. Ma, W. Lv, Y.-X. Li, B.-Z. Fan, X. Han, F.-S. Kong, J.-C. Tian, M. Cushman, and J.-H. Liang, "Design, Synthesis and Structure-Activity Relationships of Novel Macrolones: Hybrids of 2-Fluoro 9-Oxime Ketolides and Carbamoyl Quinolones with Highly Improved Activity against Resistant Pathogens," Eur. J. Med. Chem. 169, 1-20 (2019).
X.-M. Li, W. Lv, S.-Y. Guo, Y.-X. Li, B.-Z. Fan, M. Cushman, F.-S. Kong, J. Zhang, and J.-H. Liang "Synthesis and Structure-Bactericidal Activity Relationships of Non-ketolides: 9-Oxime Clarithromycin 11,12-Cyclic Carbonate Featured with Three-To-Eight-Length Spacers at 3-OH," Eur. J. Med. Chem. 171, 235-254 (2019).
K.-B. Wang, M. S. A. Elsayed, G. Wu, N. Deng, M. Cushman, and D. Yang, "Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G‑Quadruplex and Downregulate MYC, J. Am. Chem. Soc. 141, 11059-11070 (2019).
Gutierrez-Corbo, R. Alvarez-Velilla, R. M. Reguera, C. Garcia-Estrada, M. Cushman, R. Balana-Fouce, and Y. Perez-Pertejo, "Topoisomerase IB Poisons Induce Histone H2A Phosphorylation as a Response to DNA Damage in Laishmania infantum," Int. J. Parasitol.: Drugs Drug Resist. 11, 39-48 (2019).
M. Reguera, R. Alvarez-Velilla, B. Dominguez-Asenjo, C. Gutierrez-Corbo, R. Balana-Fouce, M. Cushman, and Y. Perez-Pertejo, "Antiparasitic Effect of Synthetic Aromathecins on Leishmania infantum," BMC Vet. Res. 15, Issue 1 (2019).
B.-Z. Fan, H. Hiasa, W. Lv, Z.-Y, Yang, M. Cushman, and J.-H. Liang, "Design, Synthesis and Structure-activity Relationships of Novel 15-Membered Macrolides: Quinolone/quinoline-containing Sidechains Tethered to the C-6 Position of Azithromycin Acylides," Eur. J. Med. Chem. 193, Article 112222 (2020).
Cushman, "Design and Synthesis of Indenoisoquinolines Targeting Topoisomerase I and Other Biological Macromolecules for Cancer Chemotherapy," J. Med. Chem. 64, 17572-17600 (2021).
X.-P. Liu, W. Lv, F. Zhao, J. Ding, J.-R. Zhang, F. Xue, J.-Z. Zhang, L.-Y. Liu, M. Cushman, Y. Li, and J.-H. Liang, "Design and Synthesis of Novel Macrolides Bridged with Linkers from 11,12-Positions of Macrolides," Bioorg. Med. Chem. Lett. 68, Article 128761, (2022).