‘Like a hand fitting into a glove’: Purdue-engineered compound designed to treat drug-resistant acute myeloid leukemia
June 20 2024 - 10:55AM
Researchers at Purdue University’s College of
Science have developed a patent-pending compound called HSN748
to treat drug-resistant acute myeloid leukemia (AML). AML is a
cancer that begins in bone marrow and sometimes metastasizes to the
central nervous system, liver, lymph nodes, spleen and testicles.
Herman Sintim leads the team that
has developed the compound. He is a Distinguished Professor in
Chemistry and the Richard B. Wetherill Professor of Chemistry and
Drug Discovery in the James Tarpo Jr. and Margaret Tarpo
Department of Chemistry. He also is on the faculty of
the Purdue Institute for Cancer Research and
the Purdue Institute for Drug Discovery.
Sintim’s development team collaborated
with a group including Reuben Kapur and Baskar
Ramdas at the Indiana University School of
Medicine and KinaRx Inc. to validate the
effectiveness of the compound. Kapur is the director of the Herman
B Wells Center for Pediatric Research and co-leader of the
Hematopoiesis and Hematologic Malignancies program at the IU Melvin
and Bren Simon Comprehensive Cancer Center. Ramdas is an assistant
research professor of pediatrics. KinaRx is an early-stage
biotechnology company developing novel kinase inhibitors for
cancer. It received a $2 million Small Business Innovation Research
grant from the National Institutes of Health to fund the
research.
They demonstrated that HSN748
effectively treated mice implanted with patient-derived,
drug-resistant AML with 100% survivability after 120 days. Their
co-authored paper of research results has been published in
the Journal of Clinical Investigation.
Sintim disclosed HSN748 to
the Purdue Innovates Office of Technology Commercialization,
which has applied for a patent to protect the intellectual
property.
AML metrics and traditional
treatments
The National Cancer Institute
estimates 20,800 new cases of AML will be diagnosed in 2024,
which would represent 1% of new cancer cases in the U.S. It is most
often diagnosed in people between the ages of 65 and 74, with a
median age of 69. Although uncommon, AML can occur in children. The
five-year relative survival rate is 31.9%.
Sintim said, “One of the best U.S.
Food and Drug Administration-approved drugs right now to treat AML
is called gilteritinib (Xospata). But patients have developed
genetic mutations in an enzyme called FLT3 that could render
gilteritinib ineffective.”
Ramdas said, “Despite the widespread
occurrence and clinical importance of FLT3 mutations in causing
AML, treatment options tailored to this genetic anomaly are scarce.
Our goal was to identify new and powerful inhibitors targeting the
mutations, particularly those resistant to currently approved FDA
options.”
How HSN748
works
Sintim and his team have identified
inhibitors, or blocking agents, that target FLT3 gene mutations,
the most common mutation in AML. Sintim used the three-dimensional
atomic structure of FLT3 to address the challenges of drug
resistance.
“The three-dimensional atomic
structure guided the molecular design and synthesis of HSN748 so it
fits perfectly into the active site of drug-resistant mutants of
FLT3, like a hand fitting into a glove,” Sintim said. “The
enzymatic activity of FLT3 is crucial for AML cancer cell survival,
so filling in the active site with HSN748 kills the enzyme’s
activity and also kills the cancer cells.”
Sintim continued, “Remarkably, while
all mice that had been implanted with gilteritinib-resistant human
patient AML samples and were treated with HSN748 were alive by day
120, none of the animals treated with gilteritinib survived past
day 120, demonstrating the superiority of this investigational drug
over the FDA-approved drug.”
Kapur said, “Our preclinical study
results have shown incredible promise, and we’re excited to keep
the momentum going so AML patients can have more resilient
options.”
Next development
steps
Sintim is one of the founders of
KinaRx, which has licensed HSN748 from the Purdue Innovates Office
of Technology Commercialization.
Sintim said the next stage to develop
the compound is clinical trials.
“We are at the planning stage and
looking to secure investments from different types of investors,”
he said.
Prospective funders and physicians
interested in learning about the studies can contact
Sintim.
About Purdue Innovates Office
of Technology Commercialization
The Purdue Innovates Office of
Technology Commercialization operates one of the most
comprehensive technology transfer programs among leading research
universities in the U.S. Services provided by this office support
the economic development initiatives of Purdue University and
benefit the university’s academic activities through
commercializing, licensing and protecting Purdue intellectual
property. In fiscal year 2023, the office reported 150 deals
finalized with 203 technologies signed, 400 disclosures received
and 218 issued U.S. patents. The office is managed by the Purdue
Research Foundation, which received the 2019 Innovation &
Economic Prosperity Universities Award for Place from the
Association of Public and Land-grant Universities. In 2020,
IPWatchdog Institute ranked Purdue third nationally in startup
creation and in the top 20 for patents. The Purdue Research
Foundation is a private, nonprofit foundation created to advance
the mission of Purdue University.
Contact otcip@prf.org for more information.
About Purdue
University
Purdue University is a public research
institution demonstrating excellence at scale. Ranked among top 10
public universities and with two colleges in the top four in the
United States, Purdue discovers and disseminates knowledge with a
quality and at a scale second to none. More than 105,000 students
study at Purdue across modalities and locations, including nearly
50,000 in person on the West Lafayette campus. Committed to
affordability and accessibility, Purdue’s main campus has frozen
tuition 13 years in a row. See how Purdue never stops in the
persistent pursuit of the next giant leap — including its first
comprehensive urban campus in Indianapolis, the Mitchell E.
Daniels, Jr. School of Business, Purdue Computes and the One Health
initiative —
at https://www.purdue.edu/president/strategic-initiatives.
Writer/Media
contact: Steve Martin, sgmartin@prf.org
Sources: Herman
Sintim, hsintim@purdue.edu
- Herman Sintim, Purdue University
- 2024 Herman Sintim AML chart
Steve Martin
Purdue Research Foundation
7654305150
sgmartin@prf.org