Modulation of KRAS Mutant by Inhibiting PLK1 Kinase in Cancer Therapeutics

Important Compound Classes

Title

Pyrrolo[2,3-d]pyrimidine Derivatives and Their Use in the Treatment of Cancer

Patent Publication Number

WO 2021/074251 A1

Publication Date

April 22, 2021

Priority Application

1914910.3 GB

Priority Date

October 15, 2019

Inventors

Boyle, R. G.; Walker, D. W.; Major, M. R.

Assignee Company

Sentinel Oncology Limited [GB/GB]; 181 Science Park, Milton Road, Cambridge, Cambridgeshire CB4 0GJ (GB)

Disease Area

Cancer

Biological Target

WEE1, PLK1, and KRAS

Summary

Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of the cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B and is highly expressed in numerous types of cancers that rely on the G2-M checkpoint for DNA repair. Cancers with a deficient G1 checkpoint rely on the G2-M checkpoint for survival, resulting in G2 cell-cycle arrest in response to DNA damage and allowing time for DNA repair. Cancer cells are often defective in the G1 checkpoint due to frequent p53 mutations. Consequently, the inhibition of WEE1 overrides the DNA-damage-induced cell-cycle arrest in cells with a dysfunctional p53-enforced G1 checkpoint and drives TP53 mutant cancer cells into mitotic catastrophe. Medulloblastoma, the most common type of cancerous brain tumor in children, is found to be susceptible to treatment with Wee1 inhibitors.

Unlike many brain tumors, medulloblastomas can spread through cerebrospinal fluid (CSF) and will commonly metastasize to other surfaces of the brain and to the spinal cord. A number of other types of cancer have been shown to be sensitive to Wee1 inhibition, including head and neck squamous cell carcinoma, triple-negative breast cancer, diffuse intrinsic pontine glioma (DIPG), glioblastoma, pancreatic cancer, ependymoma, acute myeloid leukemia, cervical cancer, uterine serous carcinoma, colorectal cancer, malignant melanoma, ovarian cancer, sarcoma, and small-cell lung cancer.

The Wee1 inhibitor AZD1775 is in Phase II clinical trials for women with recurrent or persistent uterine serous carcinoma or uterine carcinosarcoma. AZD1775 shows good inhibitory activity against Wee1 in cell-based assays (80 nM) and in vivo when used as the sole therapeutic agent or in combination with a further chemotherapeutic agent such as gemcitabine, cisplatin, capecitabine, or carboplatin. However, the underlying mechanism for the anticancer activity is not fully understood given that AZD1775’s single-agent activity was found to be independent of the TP53 mutational status. Also, AZD1775 is reported to have superior antiproliferative effects as a single agent compared with other similarly potent WEE1 inhibitors, which may be due to differential cellular target profiles. Polo-like kinase 1 (PLK1) performs several important mitotic functions and is a new anticancer target of AZD1775 with similar nanomolar potency. PLK1 directly regulates WEE1 activity by the phosphorylation of Ser53, which leads to ubiquitination and the subsequent proteasomal degradation of WEE1. Furthermore, AZD1775 has suboptimal absorption, distribution, metabolism, and elimination (ADME) properties, and it is highly effluxed from the brain when dosed orally, which would suggest a limiting clinical efficacy against brain malignancies.

Chemotherapeutic drugs become ineffective if the cancer cells acquire resistance to target protein that undergo mutations or have altered expression levels and the target protein can no longer be inhibited by the drug or the inhibition no longer results in therapeutic efficacy. Therefore, chemotherapeutic drugs that act on more than one target or more than one pathway are less prone to resistance. In the event that resistance is developed at one pathway, the drug is still able to exert its effect via another alternative pathway.

It has been shown that the viability of cancer cells carrying a mutant KRAS is dependent on PLK1 and that silencing PLK1 leads to the death of cells containing mutant KRAS. Compounds that inhibit PLK1 should therefore be useful in treating cancers that arise from KRAS mutations. Tumors with both p53 deficiency and high PLK1 expression may be particularly sensitive to PLK1 inhibitors. Therefore, it would also be beneficial to develop compounds that have the ability to inhibit both the Wee1 kinase and an additional kinase such as PLK1. Compounds of this Patent Highlight may be used to treat patients with cancer that is sensitive to both Wee1 and PLK1 kinase inhibition and contains a KRAS mutation.

Definitions

A = CH or N;

R¹ = −C(OH)(Alk¹)(Alk²), −N = S(O)(Alk³)(Alk⁴) and a group:

Alk¹ and Alk² are the same or different, and each is a C_1–3 saturated hydrocarbyl group;

Alk³ and Alk⁴ are the same or different, and each is a C_1–3 hydrocarbyl group;

R² = hydrogen, halogen, C_1–3 alkyl, C_1–3 alkoxy, and C_1–3 fluoroalkyl;

R³ = hydrogen, fluorine, and methyl;

R⁴ = hydrogen, fluorine, methyl, and cyano;

R⁵ = L-Cyc¹; L = −(CH₂)_m–B–(CH₂)_n–; m and n are independently selected from 0 and 1; B is absent or is selected from −C(O)N(R^c)–, S, S(O), and so forth;

Key Structures

Biological Assay

Wee1 and PLK1 kinase assays.

Biological Data

The Table below shows the ability of the exemplary compounds to inhibit human PLK1 and Wee1 kinase. Compound 17 was found to be highly orally bioavailable (>90%) with good levels of exposure observed in the brain, plasma, and CSF.

Recent Review Articles

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The author declares no competing financial interest.