Important Compound Classes
Title
Heteroaryl Compounds, Preparation Methods and Uses Thereof
Patent Publication Number
WO 2022/042630 A1
URL:https://patents.google.com/patent/WO2022042630A1/en?oq=WO+2022%2f042630+A1
Publication Date
March 3, 2022
Priority Applications
CN2020/111302 and CN2021/075781
Priority Dates
August 26, 2020, and February 7, 2021
Inventors
Dai, X.; Yang, H.; Huang, X.; Niu, H.; Han, Z.; Wang, Z.; Zhang, Q.; Liu, Y.; Jiang, Y.; Tao, L.; Weng, J.; Shi, Z.; Wang, Y.
Assignee Companies
Inventisbio CO., Ltd. [CN/CN], 1000 Zhangheng Rd., Building #63, Pudong, Shanghai 201203, China; and Inventisbio LLC [US/US], 25A Hanover Rd., Suite 340, Florham Park, NJ 07932, USA
Disease Area
Cancer
Biological Target
KRASG12D mutant
Summary
RAS (the rat sarcoma viral oncogene homologue) encodes a membrane-bound protein; it was initially described in the 1960s by Harvey and Kirsten as a retroviral oncogene involved in cells. However, it was in 1982 that the transforming properties of RAS were reported in human bladder cancer cell lines, which is considered the most frequently mutated oncogene in humans. Notably, the KRAS (Kirsten rat sarcoma viral oncogene) isoform represents 75% of RAS mutant cancers. RAS (KRAS, NRAS, and HRAS) proteins regulate key cellular pathway transmitting signals received from cellular membrane receptors to essential downstream molecules such as Raf, MEK, ERK, and PI3K. RAS protein is composed of three major domains: the G-domain, which is highly conserved between RAS isoforms and contains switch-I and switch-II loops that are responsible for GTP-GDP exchange; the C-terminal domain, also known as the hypervariable region, which is associated with significant variations among RAS isoforms; and finally, the C-terminal CaaX box, responsible for post-translational modifications.
Cancer-related mutations of KRAS are in three hotspot codons: G12, G13, and Q61, wherein G12 represents the most common mutation site. The G12D mutant is the dominant variant that occurs in the G12 position with a 35% mutation frequency, followed by G12V (29%) and G12C (21%), which has garnered increased interest to develop a new cancer therapy targeting KRASG12D mutants. KRASG12D (change of glycine at codon 12 to aspartic acid) is frequently mutated in colon adenocarcinoma, pancreatic adenocarcinoma, and lung adenocarcinoma. Targeting the switch-II pocket of KRAS (G12C) was clinically validated by Amgen (AMG510-sotorasib, approved by the FDA) and Mirati (MRTX849-adagrasib). However, targeting the KRASG12D mutation with a small molecule still remains a challenge due to its shallow pocket. Consequently, there is a huge unmet medical need for therapeutic intervention of cancer patients with RAS mutations and the development of inhibitors of the other KRAS oncogenic alleles, such as G12D.
KRAS acts as a molecular switch, which cycles between the GDP-bound inactive state and the GTP-bound active state and is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). The Son of Sevenless Homologue 1 (SOS1) is the primary and most well-studied GEF for regulating the GDP–GTP cycle of KRAS, and it interfaces with KRAS at the catalytic site, which then catalyzes the exchange of GDP to GTP.
In addition, GTP-bound KRAS can bind to an allosteric site of SOS1 and result in an enhanced SOS1 GEF function. SOS1 deletion has been shown to attenuate KRASG12D-induced myeloproliferative neoplasm and prolonge the survival of KRASG12D mice, and it also has been demonstrated to inhibit the growth of a broad range of tumor cells harboring oncogenic KRAS mutations.
The present patent highlight discloses novel RAS inhibitors, such as mutant KRAS (e.g., G12C, G12D, G12V, or G12A, more particularly G12D). The compounds and compositions are useful for treating various diseases or disorders, such as cancer or cancer metastasis.
Key Structures
Biological Assay
KRASG12D protein temperature-dependent fluorescence (TdF) binding assay; Ba/F3_KRASG12D cell proliferation assay
Biological Data
The table below shows cell growth inhibition of IC50 on
KRASG12D mutant, wherein I means ≤500 nM, II
means 500–5000 nM, and III means >5000
nM.
The author declares no competing financial interest.
References
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