Important Compound Classes
Title
Tetrahydroquinazoline Derivatives Useful as Anticancer Agents
Patent Application Number
WO/2019/155399 A1
Publication Date
15 August, 2019
Priority Application
US 62/628,350; US 62/651,796; US 62/782,408
Priority Date
09 February, 2018; 03 April, 2018; 20 December, 2018
Inventors
Chen, P.; Cheng, H.; Collins, M. R.; Linton, M. A.; Maderna, A.; Nagata, A.; Palmer, C.; Planken, S.; Spangler, J. E.; Brooun, A.
Assignee Company
Pfizer Inc.; 235 East 42nd Street New York, NY 10017, USA
Disease Area
Cancer
Biological Target
Kirsten Rat Sarcoma Oncogene Homologue (KRAS)
Summary
The invention in this patent application relates to tetrahydroquinazoline derivatives represented generally by formula I. These compounds are inhibitors of the KRAS protein and may potentially be useful for the treatment of abnormal cell growth as anticancer agents.
The Ras family of proteins is a part of the small GTPase proteins that hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). They are expressed in all types of animal cells and are involved in transmitting cell signaling pathways responsible for cell differentiation, proliferation, and apoptosis. Members of the Ras gene family include KRAS, HRAS, and NRAS. These genes are oncogenes, which means their mutation can potentially cause normal cells to become cancerous in addition to aiding cancer cells to grow and spread in the body.
The Kirsten Rat Sarcoma Oncogene Homologue (KRAS) is a part of the signaling pathway known as the RAS/MAPK (mitogen-activated protein kinase) pathway. KRAS transmits proliferation and survival signals from outside the cell to the nucleus. The KRAS molecule is activated and deactivated when it binds to GTP and GDP molecules, respectively. A growth factor mediates the activation of guanine exchange factors (GEFs). The CEFs function is to replace GDP from the inactive GDP-binding KRAS with GTP from the cytoplasm to convert it to KRAS’s active form. This active form interacts with the gamma phosphate of the GTP nucleotide via two switch regions (switch I and switch II). This in turn allows KRAS to interact with effector enzymes via a Ras Binding Domain (RBD), which start signaling cascades that alter gene expression. Binding of a GTPase activating protein (GAP) to KRAS accelerates the rate of hydrolysis of GTP into GDP. KRAS is then turned off as it binds to GDP (becomes inactive), and that stops transmitting signals to the cell’s nucleus.
Researchers discovered that Ras genes are mutated in up to 20% of human tumors (including colon, pancreas, and lung tumors) at codons 12, 13, and 61. These mutations promote the formation of the activated GTP bound form of KRAS. Lung tumors show significantly higher KRAS mutations (25–30% of all lung tumors) with about 40% of them harboring the G12C mutations thought to be promoted by carcinogens in cigarette smoke. G12C-mutated KRAS activates the MAPK pathway and promotes the growth and survival of Non-Small Cell Lung Cancer (NSCLC).
The discovery of the role of KRAS mutations in human tumors and the realization of the potential of inhibition of KRAS signaling as a therapeutic target to treat cancer has inspired researchers in both academia and industry to identify molecules that can act as Ras inhibitors.
Rapidly accelerated fibrosarcoma (Raf) proteins were first identified as retroviral oncogenes. Studies have shown that the Raf family members (namely, Raf-1, BRaf, and ARaf) are Ras effectors as well as upstream activators of the ERK pathway.
The mitogen-activated protein kinase (MAPK), a.k.a. MEK, is a serine/threonine kinase that can promote cell survival and apoptosis. It may also regulate both Raf and ERK in addition to interacting directly with KRAS.
Ras, Raf, and MAPK interact to perform a signaling cascade named Ras/Raf/MAPK pathway. The main function of this pathway is signal transduction from the extracellular milieu to the cell nucleus to activate specific genes for cell growth, division, and differentiation. It is also involved in cell cycle regulation, wound healing and tissue repair, integrin signaling, cell migration, and stimulation of angiogenesis. Thus, this signaling cascade regulates many of the cellular functions that are essential for tumorigenesis.
The activities of KRAS, BRaf, and MAPK play a central role for the Ras/Raf/MAPK signaling cascade in cancer development. For example, BRaf is frequently activated via mutation in melanoma. Studies have shown dramatic responses when melanoma was treated with either specific inhibitors of the KRAS effector BRaf alone or in combination with the inhibitors of MAPK pathway. In contrast, when MAPK inhibitors were used alone to treat cancers with mutant KRAS, the treatment did not result in similarly dramatic responses. This may be explained by the lack of an appropriate therapeutic index over normal tissues or compensatory signaling by other Ras pathways.
The above data emphasize the importance of inhibition of KRAS as an attractive therapeutic target for the treatment of cancer. To date, there are only a few developed effective KRAS inhibitors, and even fewer, if any, KRAS inhibitors have entered the clinic.
It is desirable to develop compounds that selectively bind to and inhibit mutant KRAS because these compounds would adequately inhibit the Ras signaling within the tumor to cause antitumor activity while sparing their impact on normal tissues. Recently KRAS G12C has been shown to retain cycling both biochemically and in cancer cells, creating an opportunity to disrupt its activation. Compounds that bind selectively to mutant KRAS G12C, such as the compounds of formula I in this patent application, can lock KRAS in its inactive state. These compounds may potentially provide effective therapy for cancer treatment.
Key Structures
The inventors described structures and
synthesis procedures for 42 compounds of formula I including the following
representative examples:
Biological Assay
The following assays were used to test compounds:
Mass Spectrometry Reactivity Assay (MSRA): MSRA is used to detect the formation of a covalent adduct between tested compounds and KRAS G12C
MiaPaCa2 Cell Activity Assay
H358 Cell Activity Assay
Biological Data
The biological data
obtained from testing
the above representative examples are listed in the following table:
Recent Review Articles
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Ni D.; Li X.; He X.; Zhang H.; Zhang J.; Lu S.. Pharmacol. Ther. 2019, 202, 1–17.
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O’Bryan J. P.Pharmacol. Res. 2019, 139, 503–511.
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Kohler J.; Catalano M.; Ambrogio C.. Curr. Med. Chem. 2018, 25( (5), ), 558–574.
The author declares no competing financial interest.