Technology ID
TAB-3527

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

E-Numbers
E-101-2017-0
Lead Inventor
Yang, Shyh-Ming (NCATS)
Co-Inventors
Simeonov, Anton (NCATS)
Maloney, David (NCATS)
Martinez, Natalia (NCATS)
Yasgar, Adam (NCATS)
Applications
Therapeutics
Therapeutic Areas
Ophthalmology
Oncology
Infectious Disease
Endocrinology
Dental
Cardiology
ICs
NCATS
Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Unbalanced expression levels of ALDHs have been associated with a variety of disease states such as alcoholic liver disease, Parkinson’s disease, obesity, and multiple types of cancers. ALDH1A1 also plays a major role in preserving the tumor microenvironment via differentiation, self-protection, and proliferation of cancer stem cells. The cancer cell stemness is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as an attractive 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 Aldefluor cellular activity (e.g., MIA PaCa-2, OV-90, HT-29 cancer cell lines), as well as improved pharmacokinetic (PK) properties. This chemotype also demonstrated a high degree of selectivity over other ALDH isozymes (ALDH1A2, ALDH1A3, ALDH1B1, ALDH3A1, and ALDH2) and other dehydrogenases (HPGD and HSD17ß4).

Further development of the series indicated that NCATS-101 and NCATS-102 exhibit low nanomolar potency in both enzymatic and cellular assays, demonstrate target engagement in a cellular thermal shift assay (CETSA), and can 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 NCATS-101 and NCATS-102 have good drug exposure via oral administration and should be suitable for in vivo studies or testing in other disease-relevant models.
Commercial Applications
  • Compounds and compositions that inhibit aldehyde dehydrogenases, may be used for the treatment of multiple types of cancers, inflammation, and obesity.
Competitive Advantages
  • In vitro results suggest these ALDH1A1 inhibitors may reduce the toxicity of paclitaxel-eluting stents.
Licensing Contact:
Erwin-Cohen, Rebecca
rebecca.erwin-cohen@nih.gov
Phone: 301-827-7235