Nimbus Therapeutics Publishes First-Ever High-Resolution Structure of ATP-Citrate Lyase

Nimbus Therapeutics Publishes First-Ever High-Resolution Structure of ATP-Citrate Lyase

April 3, 2019 Off By BusinessWire

Research published in Nature utilizes cryo-EM to determine
structure of critical metabolic protein

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Nimbus
Therapeutics
, a biotechnology company applying deep computational
expertise throughout drug discovery and development, today published
research in Nature describing the first high-resolution structure
of full-length human ATP-citrate lyase (ACLY), a building block of human
metabolism. Despite the ubiquitous role of ACLY in fatty acid and
cholesterol synthesis throughout the body, conventional crystallography
has not successfully elucidated its structure.


Nimbus scientists, in partnership with researchers at Columbia
University and co-founder Schrödinger, used cryo-electron microscopy
(cryo-EM) to produce the full tetrameric structure of ACLY. The cryo-EM
research was funded by Nimbus and led by Professor Liang Tong at
Columbia University. The cryo-EM data were collected at the New York
Structural Biology Center.

In addition, the publication describes potent inhibition of ACLY by a
series of computationally designed small molecules developed by Nimbus.
Inhibition of ACLY has long been recognized as a potential pathway to
treat cancer and metabolic disorders. This study describes a previously
undiscovered allosteric site of ACLY as a promising target for
inhibitory compounds, greatly enhancing the druggability of ACLY.

“This paper is a terrific example of how our work at Nimbus combines
cutting-edge technology, computational approaches and deep drug
discovery experience to generate new scientific insights,” said Jeb
Keiper, Chief Executive Officer at Nimbus. “We’re excited to continue
collaborating with experts as we interrogate new targets and deepen our
pipeline of therapies.”

“This work is a major contribution to the scientific literature, and a
remarkable demonstration of the potential of cryo-EM in drug discovery,”
said Liang Tong, Ph.D., William R. Kenan, Jr. Professor and Department
Chair at Columbia University and lead author on the study. “Together,
we’ve demonstrated how combining computational insights with
cutting-edge tools like cryo-EM may spark significant progress in cancer
and metabolic disease research.”

“Over the past decade, Nimbus has become known for major scientific
advances in protein structure elucidation and development of small
molecule therapeutic agents,” said Peter Tummino, Ph.D., Chief
Scientific Officer of Nimbus. “We look forward to sharing many more
firsts in our drug discovery programs in the months and years to come.”

The paper, entitled “An allosteric mechanism for potent inhibition of
human ATP-citrate lyase,” published online in Nature today: https://doi.org/10.1038/s41586-019-1094-6.

About Cryo-EM
Cryo-electron microscopy (cryo-EM) is a
cutting-edge microscopic imaging technique developed by
Jacques Dubochet, Joachim Frank and Richard Henderson, who were awarded
the 2017 Nobel Prize in Chemistry for this achievement. Cryo-EM allows
researchers to freeze biomolecules mid-movement and visualize processes
they have never previously seen, which is informative for both the basic
understanding of life’s chemistry and for the development of
pharmaceuticals.

About Nimbus Therapeutics
Nimbus Therapeutics is a
biotechnology company headquartered in Cambridge, Massachusetts (USA).
Nimbus is pioneering the application of highly advanced computational
technologies to the design and development of novel treatments for
substantial and underserved human diseases. The company’s focus on
metabolic diseases, cancer and immune-inflammatory disorders reflects
the mechanistic relationship between these disorders, and Nimbus’
ability to rapidly tackle well-validated targets as well as those that
have proven intractable to others. The company’s LLC/subsidiary
architecture enables diverse and synergistic partnerships to deliver
breakthrough medicines. To learn more, please visit www.nimbustx.com.

Contacts

Lisa Raffensperger, (617) 903-8783
Ten Bridge Communications
[email protected]