Targeting the “Undruggable” Driver Protein, KRAS^G12D, as Potential Therapy in Prostate Cancer

Abstract

In spite of the progress made in the development of KRAS^G12C inhibitors, there is still continued interest to develop inhibitors of other KRAS such as KRAS^G12D for the treatment of diseases, including prostate cancer, colorectal cancer, and non-small-cell lung cancer. This Patent Highlight provides exemplary compounds having activity as inhibitors of G12D mutant KRAS protein.

Important Compound Classes

Title

Heterocyclic Compounds and Methods of Use

Patent Publication Number

WO 2023/018810 A1 (URL: https://patentscope2.wipo.int/search/en/detail.jsf?docId=WO2023018810&_cid=JP2-LEU25G-45528-1).

Publication Date

February 16, 2023

Priority Application

US 63/299,667

Priority Date

January 14, 2022

Inventors

Lanman, B. A.; Zhao, W.; Wurz, R. P.; Navaratne, P.; Pettus, L.; Yamano, M. M.; Chen, N.; Rahimoff, R.; Manoni, F.; Stellwagen, J.

Assignee Company

Amgen Inc. [US/US]; One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.

Disease Area

Cancer

Biological Target

KRAS^G12D

Summary

Pancreatic cancer (PCa) is a malignant tumor with a high incidence and poor prognosis and was estimated to have caused more than 450,000 deaths in 2020, with a case fatality rate of over 90%.^ref1 The oncogenic driver plays an important role in the proliferation and metastasis of the tumors. The lack of screening and early metastasis are major reasons for the high mortality rate found in PCa cases. In pancreatic ductal carcinoma (PDAC), the most common subtype of PCa, KRAS (the Kirsten rat sarcoma viral oncogene homolog) is the most predominant mutated gene (more than 80%). Most PDACs have been identified to contain four driver mutations: KRAS, the tumor suppressor protein 53 (TP53), the cyclin-dependent kinase inhibitor 2 (CDKN2A), and the small mothers against decapentaplegic homolog 4 (SMAD4). The incidence of the KRAS mutation in PDAC could reach up to an astonishing 86%.

Consequently, targeted KRAS therapy will be key to improving the poor prognosis of PDAC. However, KRAS proteins have maintained the reputation of being “undruggable” for over a decade due to their special molecular structures and biological characteristics, which makes any therapy targeting downstream genes challenging. Fortunately, the discovery of a manageable therapeutic approach emerged in the advent of KRAS^G12C inhibitors; the covalent inhibitors bond to the switch-II pockets of the KRAS^G12C protein. This has culminated in the approval by the U.S. FDA of the KRAS^G12C inhibitor sotorasib for the treatment of patients suffering from KRAS^G12C-driven cancers. Due to the high incidence of PDAC, developing KRAS^G12D/V inhibitors and KRAS mutations has become the focus of attention for academic and industrial research.

KRAS is a key node in the MAPK signal transduction pathway and a transforming factor in a network of parallel effector pathways. Progress has been made in the development of inhibitors of upstream and downstream nodes in the MAPK pathway, including BRAF, EGFR, and MOK; however, the KRAS protein has proven resistant to readily available inhibitors that induce direct inhibition. KRAS is a G-protein that couples extracellular mitogenic signaling to intracellular, pro-proliferative responses and serves as an intracellular “on/off” switch. The binding of GTP to KRAS is induced by mitogen stimulation, which causes a conformational change that enables the interaction of KRAS with downstream effector protein and cellular proliferation. Mutations in KRAS impair the regulated cycling of KRAS between the GDP-bound, non-proliferative state and the GTP-bound, activating state, which leads to the accumulation of the GTP-bound active state and dysregulated cellular proliferation.

In spite of the progress made in the development of KRAS^G12C inhibitors, there is still continued interest to develop inhibitors of other KRAS, such as KRAS^G12D, KRAS^G12V, KRAS^G12A, or KRAS^G12S, in the treatment of diseases such as cancer. The disclosure in WO 2023018810 A1 provides compounds having activity as inhibitors of G12D mutant KRAS protein. In addition, it provides methods of treating certain disorders, such as cancer, including but not limited to non-small-cell lung cancer (NSCLC), colorectal cancer, and/or PCa.

Key Structures

Biological Assay

KRAS^G12D TR-FRET assay, KRAS^G12D coupled nucleotide exchange assay, and phosphor-ERK1/2 MSD assay.

Biological Data

The table below shows biochemical and cellular activity for exemplary compounds.

Recent Reviews

See refs (1−6).

The author declares no competing financial interest.