Important Compound Classes
Title
Polycyclic Compounds and Methods for the Targeted Degradation of Rapidly Accelerated Fibrosarcoma Polypeptides
Patent Publication Number
WO 2020/051564 A1
Publication Date
March 12, 2020
Priority Application
US 62/728,581
Priority Date
September 7, 2018
Inventors
Crew, A. P.; Hornberger, K. R.; Wang, J.; Crews, C. M.; Jaime-Figueroa, S.; Dong, H.; Qian, Y.; Zimmerman, K.
Assignee Company
Arvinas Operations, Inc., 5 Science Park, New Haven, Connecticut 06511, USA and Yale University, Two Whitney Avenue, New Haven, Connecticut 06510, USA.
Disease Area
Cancer
Biological Target
Rapidly Accelerated Fibrosarcoma (RAF).
Summary
The rapidly accelerated fibrosarcoma (RAF) kinases are a family of three serine/threonine specific protein kinases, which play critical roles in multiple cellular processes, including cell cycle progression, cell proliferation, cell metabolism, cell migration, cell differentiation, and apoptosis. In mammals, the classic RAS-RAF-MEK-ERK signaling pathway is conserved, and the mitogen-activated protein kinase (MAPK) signaling pathway is of great importance to cellular biological functions. The RAF family contains three members: ARAF, BRAF, and CRAF, binding with RAS as the upstream activator and mediating the MAPK signaling transduction to MEK. The transmission of signal is achieved by the transformation from the RAS.GDP (inactive) to RAS.GTP (active) with the help of extracellular signals, which in turn triggers several downstream cascades, including the RAF/MEK/ERK pathway. The hyperactivation of ERK signaling due to mutations in genes encoding receptor tyrosine kinases, RAS, BRAF, CRAF, MEK1, or MEK2 is associated with 30% of human cancers, including melanoma, breast cancer, ovarian cancer, colon cancer, thyroid cancer, prostate cancer, and so forth. Furthermore, deregulation of this pathway is considered to be driven by mutations of BRAF and its RAS activator, and RAS mutations are associated with 27% of all human cancers. Naturally, the MAPK pathway is frequently dysregulated in many cancer-harboring RAS mutations, resulting in constitutive activation of the pathway, uncontrolled proliferation, and decreased cellular sensitivity to agents that could originally induce apoptosis.
Many inhibitors have been developed to modulate RAS activity; however, significant challenges still exist to target RAS directly. The lack of well-defined druggable pockets and cavities on the RAS surface made RAS an “undruggable” target. The problem is exacerbated by frequently mutated RAS genes in cancer cells. One druggable approach is disturbing the signal transduction between RAS proteins and downstream effectors, which serves as a strategy to develop novel RAS-driven therapies.
There exists great need for an effective treatment for disease associated with overexpression or aggregation of RAF or the overactivation of RAF. For instance, current BRAF inhibitors such as vemurafenib and dabrafenib may only target the V600 mutant BRAF. Consequently, diseases or disorders in melanoma, lung cancer, pancreatic cancer, etc. may have different BRAF mutations that are insensitive to the currently marketed agents. In addition, resistance mutations can emerge in response to BRAF/MEK inhibitor therapy. In melanoma patients, the p61 splice variant can emerge when treated with BRAF/MEK inhibitor therapy, which may leave these patients with no clinical options. Currently marketed agents also bind to and cause paradoxical activation of wild-type BRAF, which results in clinical complications. The family of hypoactive Class I BRAF mutants that signal through heterodimerization with CRAF, constitute 40% of BRAF mutations in non-small cell lung cancer (NSCLC), which cannot be targeted with any currently approved or clinical-stage BRAF inhibitors.
This Patent Highlight describes bifunctional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation. The bifunctional or proteolysis targeting chimeric (PROTAC) compounds modulate ubiquitination of a variety of polypeptides and other proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described. An effective amount of these compounds may be used for the treatment or amelioration of a disease condition, such as cancer, including colorectal cancer, prostate cancer, renal cell carcinoma, ovarian cancer, pancreatic cancer, lung cancer, thyroid cancer, pilocytic astrocytoma, gastric cancer, hepatocellular, and so forth.
The bifunctional or PROTAC compounds comprise an E3 ubiquitin ligase binding moiety (ligand for an E3 ubiquitin ligase or “ULM” group) and a moiety that binds a target protein (protein/polypeptide targeting ligand or “PTM” group) such that the target protein/polypeptide is placed in close proximity to the ubiquitin ligase to effect degradation of that protein.
Key Structures
Biological Assay
In-cell Western cellular assay for target protein degradation. A375 cells were cultured in ATCC DMEM + 10% FBS in 12- or 96-well plates and treated with PROTAC compounds. Subsequent manipulations were followed by quantification using either the BioRad Image Lab 5 Software or LICOR Odyssey Software.
Biological Data
The table below shows degradation activity
of BRAF, including Class I BRAF mutant (V600E) protein in cells, where
DC50: A < 10, 10 ≤ B ≤ 50 and Dmax: A ≥ 70, 50 ≤ B ≤ 70.
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The author declares no competing financial interest.