Novel Amide Compounds as KIF18A Inhibitors for Treating Cancer

Important Compound Classes

Title

KIF18A Inhibitors

Patent Publication Number

WO 2021/026098 A1

Publication Date

February 11, 2021

Priority Application

US 62/882,255

Priority Date

August 2, 2019

Inventors

Tamayo, N. A.; Banerjee, A.; Chen, J. J.; Bourbeau, M. P.; Kallar, M. R.; Low, J. D.; Minatti, A. E.; Nguyen, T. T.; Nishimura, N.; Pettus, L. H.; Walton, M. C.; Xue, Q. M.; Allen, J. G.

Assignee Company

Amgen Inc., USA

Disease Area

Cancer

Biological Target

KIF18A

Summary

Cancer is one of the most widespread diseases afflicting mankind and a major cause of death worldwide. Cancer is often characterized by unregulated cell proliferation. Damage to one or more genes, responsible for the cellular pathways, which control progress of proliferation through the cell cycle and centrosome cycle, can cause the loss of normal regulation of cell proliferation. These deregulated genes can code for various tumor suppressor or oncogene proteins, which participate in a cascade of events leading to unchecked cell-cycling progression and cell proliferation. Various kinase and kinesin proteins have been identified, which play key roles in the cell cycle, mitotic regulation, and progression of normal dividing cells and cancer cells.

Kinesins are molecular motors that play important roles in cell division, intracellular vesicles, and organelle transport. Mitotic kinesin plays roles in several aspects of spindle assembly, chromosome segregation, centrosome separation, and dynamics. Human kinesins are categorized into 14 subfamilies based on sequence homology within the so-called “motor domain”; this domain’s ATPase activity drives unidirectional movement along microtubules (MT). The nonmotor domain of these proteins is responsible for cargo attachment; a “cargo” can include any one of a variety of different membranous organelles, signal transduction scaffolding systems, and chromosomes. Kinesins use the energy of ATP hydrolysis to move cargo along polarized microtubules. Thus, kinesins are often called “plus-end” or “minus-end” directed motors.

The KIF18A gene belongs to the Kinesin-8 subfamily and is a plus-end-directed motor. KIF18A is believed to influence dynamics at the plus end of kinetochore microtubules to control correct chromosome positioning and spindle tension. Depletion of human KIF18A leads to longer spindles, increased chromosome oscillation at metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells. KIF18A appears to be a viable target for the treatment of cancer. KIF18A is overexpressed in various types of cancers, including but not limited to colon, breast, lung, pancreas, prostate, bladder, head, neck, cervix, and ovarian cancers. Further, genetic deletion, knockdown, or inhibition of KIF18A affects the mitotic spindle apparatus in cancer cell lines. Particularly, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote cell death in mitosis via apoptosis, mitotic catastrophe, or multipolarity driven lethality or death after mitotic slippage in interphase.

The present application describes a series of novel amide compounds as KIF18A inhibitors which are useful for the treatment of cancer. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = a group -Z-R₁₂ wherein Z is absent, -C_0–4alk-S-C_0–4alk-, -C_0–4alk-S(C=O)-C_0–4alk-, -C_0–4alk-SO₂-C_0–4alk-, -C_0–4alk-NR₁₁-C_0–4alk-, -C_0–4alk-NR₁₁SO₂-C_0–4alk-, -C_0–4alk-SO₂NR₁₁-C_0–4alk-, -C_0–4alk-NR₁₁SO₂NR₁₁-C_0–4alk-, -C_0–4alk-O-C_0–4alk-, -C_0–4alk-(C=O)-C_0–4alk-, -C_0–4alk-(C=O)-O-C_0–4alk-, -C_0–4alk-(C=O)-NR₁₁-C_0–4alk-, -C_0–4alk-NR₁₁(C=O)-C_0–4alk-, -C_0–4alk-S(C=O)(=NH)-, -N=S(=O)<, -(C=O)-, or -C(N=OH)-;

R₂ = a group -Y-R₁₃, wherein Y is -C_0–4alk-S-C_0–4alk-, -C_0–4alk-S(C=O)-C_0–4alk-, -C_0–4alk-SO₂-C_0–4alk-, -C_0–4alk-NR_13c-C_0–4alk-, -C_0–4alk-SO₂NR_13c-C_0–4alk-, -C_0–4alk-NR_13cSO₂-C_0–4alk-, -C_0–4alk-S(=O)(=NH)-, -C_0–4alk-O-C_0–4alk-, -C_0–4alk-(C=O)-C_0–4alk-, -C_0–4alk-(C=O)-O-C_0–4alk-, -C_0–4alk-(C=O)-NR_13c-C_0–4alk-, -C_0–4alk-NR_13c(C=O)-C_0–4alk-, or -N=S(=O)<;

R₃ = H, halo, C_1–4alk-, or C_1–4haloalk-;

R₄ = H, halo, C_1–4alk-, or C_1–4haloalk-;

R₅ = H, halo, C_1–4alk-, or C_1–4haloalk-;

R₆ = H, halo, C_1–4alk-, or C_1–4haloalk-;

R₇ = H, halo, C_1–4alk-, or C_1–4haloalk-;

R₈ = H, halo, C_1–4alk-, or C_1–4haloalk-;

R₉ = H, halo, C_1–4alk-, or C_1–4haloalk-;

L = -(C=O)-NR₁₀- or -NR₁₀-(C=O)-; and

R₁₀ = H or C_1–4alk-.

Key Structures

Biological Assay

The human KIF18A ATPase assay was performed. The microtubule-stimulated ATPase activity assay is used to measure KIF18A enzyme activity after treatment with compound. The compounds described in this application were tested for their ability to inhibit KIF18A. The KIF18A ATPase IC₅₀ values (μM) are shown in the following Table.

Biological Data

The Table below shows representative compounds that were tested for KIF18A ATPase inhibition. The biological data obtained from testing representative examples are listed in the following Table.

Claims

Total claims: 35

Compound claims: 29

Pharmaceutical composition claims: 1

Method of treatment claims: 3

Method of reducing/inhibiting claims: 2

Recent Review Articles

• 1.Konjikusic M. J.; Gray R. S.; Wallingford J. B.. Dev. Biol. 2021, 469, 26.
• 2.Lin Y.; Wei Y.; She Z.. Chromosoma 2020, 129, 99.
• 3.Liang Y.; Yang W.. Gene 2019, 684, 1.
• 4.Vicente J. J.; Wordeman L.. Curr. Opin. Cell Biol. 2019, 60, 36.
• 5.Sheng L.; Hao S.; Yang W.; Sun Y.. Gene 2018, 678, 90.

The author declares no competing financial interest.