New Hope for Leukemia: Discovery of Precision-Designed Molecules
Research Summary: A precision chemotype based on adamantane–quinoxalone hybrids that selectively targets t(8;21) AML cells, sparing other leukemia subtypes, solid tumors, and normal cells, highlighting its potential as a targeted therapeutic agent.
Author Interview
Ms. Sangita Dattatray Shinde graduated in B-Pharmacy from the School of Pharmacy, Swami Ramanand Teerth Marathwada University, Nanded, Maharashtra (2018), and received her M.S. (Pharm.) in Medicinal Chemistry from NIPER-Hyderabad (2020) under the supervision of Dr. Nagula Shankaraiah. She is currently pursuing her Ph.D. under Dr. Dinesh Kumar at NIPER-Ahmedabad. Her research interests include the construction and functionalization of bioactive heterocycles via sustainable synthetic designs.
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Lab: Dr. Dinesh Kumar, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India
What was the core problem you aimed to solve with this research?
Acute Myeloid Leukemia (AML) is a globally prevalent blood cancer with subtypes defined by genetic abnormalities. One subtype, t(8;21) AML, results from a translocation between chromosomes 8 and 21. Despite advancements in treatment, t(8;21) AML outcomes remain poor due to drug resistance, relapse, and nonspecific chemotherapy toxicity. There is a critical need for targeted therapies that selectively attack t(8;21) AML cells without harming normal tissues.
How did you go about solving this problem?
The precision chemotype was synthesized via radical hydro-adamantylation of quinoxalones under metal- and light-free conditions. This green synthesis method reduces residual toxicity, avoids contamination, and enhances scalability.
Biological studies, including cancer assays, RNA sequencing, and proteomics, showed that compound 3j selectively kills t(8;21) AML cells by disrupting vital growth pathways. The compound was minimally toxic to other leukemias, solid tumors, and healthy cells—making it a highly selective candidate for targeted therapy.
How would you explain your research outcomes (Key findings) to the non-scientific community?
AML is a serious blood cancer, and the t(8;21) variant makes up about 10–15% of cases. Despite treatments, many patients relapse or suffer from side effects due to the non-specific nature of chemotherapy.
We discovered a compound that targets only t(8;21) AML cells, sparing other cancer types and normal cells. This means fewer side effects and better chances of recovery. The compound is also synthesized in an eco-friendly and scalable way, which could make it easier to bring into clinical use.
The compound selectively targets specific leukemic cells while sparing others, offering hope for a safer and more precise leukemia treatment. Additionally, these compounds may serve as tools to understand AML better and discover new treatment strategies.
What are the potential implications of your findings for the field and society?
This research introduces adamantane–quinoxalone hybrids that precisely disrupt pathways supporting t(8;21) AML cell growth, without harming other cells. They could become powerful targeted therapies.
These findings support the development of new treatments, either standalone or in combination with current therapies. They may also help scientists uncover hidden mechanisms of leukemia, leading to even more breakthroughs.
Overall, this work contributes to precision oncology and the future of personalized cancer treatments.
What was the exciting moment during your research?
One of the most thrilling moments came during RNA sequencing analysis. We saw a dramatic shift in gene expression: tumor-promoting genes like MYCN, BCL6, PIM1, CDK1, and others were downregulated, while differentiation-promoting genes like CSF3R, KLF2, and DACH1 were upregulated. This indicated that compound 3j could actually reprogram leukemic cells to stop growing and start maturing—a transformative discovery that validated our therapeutic approach.
Paper Reference
Shinde, S. D.; Chamoli, A.; Uppalapati, S. S.; Sharma, J.; Kumar, V.; Mandoli, A.; Kumar, D. Adamantane-Quinoxalone Hybrids: Precision Chemotypes and Their Molecular Mechanisms in Acute Myeloid Leukemia. J. Med. Chem. 2025, 68, 7693–7706.
https://doi.org/10.1021/acs.jmedchem.5c00262
