Substituted Quinoline Analogs as Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors

Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Unbalanced biological activity of ALDHs has been associated with a variety of disease states such as alcoholic liver disease, Parkinson’s disease, obesity, and Cancer. Increased expression of ALDH1A1 has been identified in a wide-range of human cancer stem cells and is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as a therapeutic target.

We performed a systematic medicinal chemistry optimization and biological characterization of newly designed quinoline series that ultimately led to potent ALDH1A1 inhibitors with excellent enzymatic potency and cellular activity (e.g. MIA PaCa-2, OV-90, HT-20 cancer cell lines), as well as improved eADME properties. This chemotype demonstrated a high degree of selectivity over other ALDH isozymes (ALDH1B1, ALDH3A1, and ALDH2) and other dehydrogenases (HPGD and HSD17β4).

Further development of the series indicated that NCT-505 and NCT-506 exhibit low nanomolar potency in both enzymatic and cellular assays, demonstrate target engagement in a cellular thermal shift assay (CETSA) and are capable to inhibit the formation of 3D spheroid cultures of OV-90 ovarian cancer cells. In addition, lead compounds potentiated the cytotoxicity of Paclitaxel in SKOV-3-TR, a Taxol-resistant ovarian cancer cell line, which suggest the potential feasibility of combined treatment with existing cancer drugs. PK studies demonstrated that NCT-505 and NCT-506 have reasonable drug exposure via PO administration and should be suitable for in vivo proof of concept animal studies or other disease-relevant models and can be used for a better understanding of the physiological and pathophysiological actions of this enzyme.

Potential Commercial Applications: Competitive Advantages:
  • Compounds and compositions that inhibit aldehyde dehydrogenases, may be used for the treatment of various conditions such as cancer, inflammation, or obesity.
  • Reducing the toxicity of paclitaxel eluting stents.


Shyh Yang (NCATS)  ➽ more inventions...

Anton Simeonov (NCATS)  ➽ more inventions...

David Maloney (NCATS)  ➽ more inventions...

Natalia Martinez (NCATS)  ➽ more inventions...

Adam Yasgar (NCATS)  ➽ more inventions...

Intellectual Property:
US Application No. 62/578,899
PCT Application No. PCT/US2018/058257
US Application No. 16/760,345

Yang SM, et al. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1). J Med Chem. 2015 Aug 13;58(15):5967-78. PMID 26207746
Yasgar A, et al. A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. PLoS One. 2017 Jan 27;12(1). PMID 28129349
Yang SM, et al. Discovery of Orally Bioavailable, Quinoline-based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity. Submitted.

Collaboration Opportunity:

This invention is available for licensing and/or co-development to achieve expeditious commercialization of results of federal funded research and development.

Licensing Contact:
Rebecca Erwin-Cohen, Ph.D.
Phone: 301-827-7235

OTT Reference No: E-101-2017-0
Updated: Feb 27, 2018