Targeting KRAS^G12D Mutations: Discovery of Small Molecule Inhibitors for the Potential Treatment of Intractable Cancers

Abstract

The KRAS^G12D mutation, frequently found in pancreatic cancer, is representative of various challenging cancers and is a crucial target for chemotherapy drug development. Researchers are exploring highly selective and potent small molecule inhibitors of KRAS^G12D to meet the needs of patients with this mutation. The Patent Highlight reveals novel compounds capable of inhibiting KRAS^G12D proteins, potentially useful in treating KRAS^G12D-associated diseases, including cancers.

Important Compound Classes

Titles

KRAS^G12D Inhibitors and Uses Thereof

Patent Publication Number

WO 2023/001141 A1

URL: https://patents.google.com/patent/WO2023001141A1/en?oq=WO+2023%2f001141+A1

Publication Date

January 26, 2023

Priority Applications

CN PCT/CN2021/143176

Priority Dates

December 30, 2021

Inventors

Zhou, D.; Wang, Z.; Cheng, Z.; Chen, S.

Assignee Companies

Shanghai Zion Pharma Co. Limited [CN/CN]; 8F, #805, Chamtime Tower B, 2889 Jinke Road, Pudong New District, Shanghai 200210, China

Disease Area

Cancer

Biological Target

KRAS^G12D

Summary

RAS encompasses a family of small guanosine triphosphatase (GTPase) proteins involved in cellular signal transduction. RAS proteins act as molecular switches, controlling various cellular functions such as cell growth, differentiation, and survival. There are three main RAS isoforms in humans: HRAS, KRAS, and NRAS. These proteins are highly homologous in sequence and structure, but they are encoded by separate genes. RAS proteins cycle between an active (GTP-bound) state and an inactive (GDP-bound) state, with the active state triggering downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase (PI3K) pathway.

RAS is also known as a proto-oncogene because activating mutations in RAS genes can result in the continuous stimulation of cellular signaling pathways, leading to uncontrolled cell growth and proliferation. This can contribute to the development of various types of cancers. RAS mutations are found in approximately 30% of all human cancers, making RAS isoforms among the most frequently mutated oncogenes in human malignancies.

KRAS, one of the most frequently mutated RAS isoforms, has been the subject of extensive research in recent years. KRAS is a prominent oncogene that has been shown to drive tumorigenesis, modulate numerous genetic regulatory mechanisms, and form an extensive tumorigenesis network. The KRAS gene encodes a 21 kDa protein, which is part of the RAS/MAPK pathway. The KRAS protein is a GTPase, binding guanine nucleotides GDP and GTP with high affinity and hydrolyzing GTP to GDP. The GDP/GTP cycling is strictly regulated by a diverse family of multi-domain proteins, including guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs stimulate GDP dissociation and GTP association, activating RAS proteins, while GAPs accelerate intrinsic GTP hydrolysis, inactivating RAS.

The active form of KRAS is GTP-bound, and downstream signaling effectors specifically bind to this form. When bound to GDP, KRAS is inactivated and does not relay signals to the cell’s nucleus. Cancer-promoting KRAS mutations commonly occur at codon 12, 13, or 61, with G12 being the most frequently mutated residue (89%). G12 mutations typically result in aspartate (G12D, 36%), valine (G12V, 23%), or cysteine (G12C, 14%) substitutions.

KRAS mutations are present in up to 25% of cancers, with oncogenic variants having different prevalence rates across cancer types. In pancreatic ductal adenocarcinoma cases, the most common KRAS alteration is the G12D substitution. The G12D variant is also a major target for drug discovery efforts, such as Mirati’s lead compound MRTX1133, which is in clinical trials for patients with advanced solid tumors harboring a KRAS^G12D mutation.

The KRAS^G12D mutation is commonly observed in pancreatic cancer which can be considered representative of various intractable cancers. KRAS^G12D represents an important target for chemotherapy drug development. Researchers are actively investigating highly selective and potent small molecule inhibitors of KRAS^G12D to address the unmet needs of patients with this mutation. This patent discloses novel compounds that are capable of inhibiting KRAS^G12D proteins. Consequently, these compounds are potentially useful in the treatment of KRAS^G12D-associated diseases such as cancers.

Key Structures

Biological Assay

Phospho-ERK 1/2 assay, KRAS^G12D 3D CellTiter-Glo proliferation assay, and in vivo oral bioavailability assay were performed.

Biological Data

The table below shows p-ERK IC₅₀ values and bioavailability data of the exemplary compounds.

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.