Combination of Cyclin-Dependent Kinase 4 Inhibitors and Androgen Receptor Inhibitors as Cancer Therapy

Important Compound Classes

Title

Combination Therapy

Patent Publication Number

WO 2022/034504A1

URL: https://patents.google.com/patent/WO2022034504A1/en?oq=WO+2022%2f034504+A1

Publication Date

February 17, 2022

Priority Application

US63/065,160

Priority Date

August 13, 2020

Inventors

Anders, L.; Kim, K. H.; Li, D.; Mcmillan, E. A.; Rollins, R. A.; Veeneman, B. A.

Assignee Company

Pfizer Inc., 235 East 42nd Street, New York, New York 10017 (US); Astellas Phar; 2-5-1, Nihonbashi-Honcho, Chuo-Ku, Tokyo, 103-8411 (JP)

Disease Area

Cancer

Biological Target

Cyclin-dependent kinase 4/6 (CDK-4/6) and androgen receptor (AR)

Summary

The invention in this patent application relates to a combination therapy that may be useful for treating cancer. The combination therapy consists of a cyclin-dependent kinase 4 (CDK4) inhibitor of Formula 1 and an androgen receptor (AR) inhibitor selected from several known approved inhibitors, such as enzalutamide, N-desmethyl enzalutamide, darolutamide, apalutamide, and abiraterone. The combination therapy may optionally include an additional anti-cancer agent. This combination therapy may potentially treat several kinds of cancer, including, but not limited to, prostate cancer, breast cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, and ovarian cancer.

The AR is a member of the nuclear receptor superfamily that functions as a ligand-activated transcription receptor (TR). It is activated in the cytoplasm by the androgenic hormones testosterone and dihydrotestosterone (known collectively as androgens). Once activated, it translocates to the nucleus, where it binds to a specific sequence of DNA and regulates gene expression. Studies have determined a role for the AR in promoting certain cancers, including, but not limited to, prostate cancer, certain breast cancers, certain lung cancers, hepatocellular carcinoma, and salivary gland tumors. Activation of the AR in patients with advanced prostate cancer by its binding to androgens stimulates the growth of prostate cancer cells. Therefore, the initial therapy for advanced prostate cancer includes one of two androgen-reducing treatments:

• surgical removal of both testicles (bilateral orchiectomy)

• use of androgen deprivation therapies (ADT) such as luteinizing hormone-releasing hormone (LHRH) agonist or antagonist drugs to lower the body’s production of testosterone

However, prostate cancer advances in some patients over time to castration-resistant prostate cancer (CRPC), which is a more aggressive form that is resistant to the hormone deprivation therapies. This resistance is thought to be related to amplification and/or over-expression of the AR. This aggressive form of prostate cancer continues to grow and does not respond to extreme reduction of testosterone production. The progression to CRPC stage may be determined by increased levels of prostate-specific antigen (PSA), imaging tests, or clinical symptoms.

Anti-androgens are medications that function to suppress the androgen activity through a number of different mechanisms. Some anti-androgens function by lowering the production of androgens, while others block the AR to limit the body’s ability to use the produced androgens. Abiraterone acetate (marketed as Zytiga) is a steroidal anti-androgen approved for the treatment of CRPC. It blocks the biosynthesis of androgens by inhibiting the cytochrome P450 17A1 (CYP17A1) enzyme. Another example of anti-androgens is the AR inhibitor (or antagonists) enzalutamide (marketed as Xtandi), which is also approved for the treatment of metastatic CRPC. However, despite the availability of several anti-androgens that show initial response, the prostate cancer may relapse and develop therapeutic resistance to these treatments by yet not fully understood mechanisms.

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases perform key functions in regulating cell progression and proliferation. Some (CDKs 1–4, 6, 10, 11) perform their functions directly, while others (CDKs 3, 5 and 7–9) act indirectly by activating other CDKs or regulating transcription or neuronal functions. The activation of CDK is promoted through binding to regulatory subunits, known as cyclins, followed by phosphorylation. Cyclins are divided into four general classes (G1, G1/S, S, and M cyclins). These subunits are expressed at variable levels based on their functions at different stages of the cell cycle. The activated cyclin/CDK catalytic unit is represented by its two subunits, such as cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, and cyclin D/CDK6. These and other activated heterodynes are important regulators of the cell cycle progression.

Combinatorial targeted therapy has emerged in recent years as a promising strategy to enhance the anti-tumor activity of monotherapy and to counteract acquired cancer drug resistance. Despite several disappointing results from earlier clinical trials of CDK inhibitors as monotherapy cancer treatment, there is promising evidence that combining a CDK inhibitor with another anti-cancer agent appears to maximize the anti-tumor efficacy of the targeted therapy.

Recently, the FDA has approved several CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer in combination with endocrine therapy. This new advancement in cancer treatment was realized based on the observation of enhanced efficacy in prolonging progression-free survival (PFS) in patients treated with a drug combination compared to patients treated with endocrine therapy alone. In vitro studies have also shown that combining CDK4/6 inhibitors with estrogen receptor (ER) blockers has promoted improved anti-proliferative effects against HR+/HER2– breast cancer cells.

CDK4/6 inhibitors have displayed significant clinical efficacy on their own in HR+/HER2– advanced or metastatic breast cancer. However, a possible drawback is the development of primary or acquired resistance over time, which limits their effectiveness. Studies have determined that the expression of cyclin D1, the activating subunit for CDK4, is positively regulated by the ER, thus promoting the cell cycle entry. This finding suggests that the benefit of the combination treatment may have been, at least in part, the result of convergent effects of CDK4/6 and ER inhibitors on the cyclin D1/CDK4/6 complex in breast cancer cells.

The AR is another oncogene that can stimulate the expression of cyclin D1 and activate CDK4 in prostate cancer cells. In vitro and in vivo studies on the CDK4/6 inhibitor palbociclib have provided evidence implicating AR activation in promoting cell cycle progression and cell proliferation leading to CDK4/6 inhibitor resistance. These studies have also shown that simultaneous inhibition of CDK4/6 and AR may reverse resistance to palbociclib and suggested the inhibition of AR as a novel therapeutic strategy to stop or minimize CDK4/6 inhibitor resistance in cancer.

The invention in this patent application describes a potentially improved therapy for the treatment of cancers by using a drug combination consisting of the following:

• a CDK4 inhibitor of Formula 1 such as Compound A, a potent and selective inhibitor of CDK4

• an AR inhibitor selected from several known and approved inhibitors such as the examples shown below

• possibly an additional anti-cancer agent and/or an androgen deprivation therapy (ADT)

This combination therapy may potentially provide effective treatment to several cancers, including, but not limited to, prostate cancer, breast cancer, lung cancer, bladder cancer, and ovarian cancer. It may also have more advantages such as improved efficacy overusing single therapeutic agents alone, improved dosing schedule, reducing side effects, and overcoming drug resistance.

Key Structures

The inventors have mentioned the following structures as potential combination partners as described in the patent application.

CDK4 Inhibitors

Compound A is the only mentioned example of Formula 1. It has been reported previously in two patent applications, WO 2019/207463 A1 and US 2019/0330196 A1.

Androgen Receptor (AR) Inhibitors

The inventors mentioned the following known and approved anti-androgens, also known as AR inhibitors, as possible partners of the combination therapy claimed in this patent application.

Biological Assays

• 1.Multicellular Tumor Spheroid (MCTS) Growth Assay in Human AR+ Prostate Cancer Cells (LNCaP)
• 2.In Vitro Screen in C4–2 Human Prostate Cancer Cells
• 3.In Vitro Screen in VCaP Human Prostate Cancer Cells

Biological Data

The data obtained from assay 1 are listed in the table below and show the measurements of percent of spheroid growth inhibition (SGI%) for single agent and combination treatments.

The author declares no competing financial interest.