Antiproliferative necroptosis inducers or autophagy inhibitors or a combination thereof

​​​​​​Background

Breast cancer is the leading cause of cancer-related deaths in women worldwide, and triple negative breast cancer (TNBC) accounts for approximately 15-20% of these cancers. TNBC tumors do not express three key therapeutically relevant cell-surface receptors: estrogen receptor (ER), progesterone receptor (PR), and overexpression of the human epidermal growth factor receptor 2 (Her2). The absence of these receptors significantly decreases treatment success since most of the currently approved breast cancer treatments mainly target one of the receptors. Furthermore, TNBC tumors have unique clinical, molecular and pathological characteristics resulting in higher relapse rates and worse prognosis when compared to non-TNBC tumors. There is currently no targeted therapy for TNBC. The most frequently used treatment regimen is surgery, with adjuvant chemotherapy and radiation therapy. This therapeutic regimen is ineffective once the tumor spreads to other organs. Also, most TNBC patients relapse after initial therapy resulting in even poorer prognosis. There is an urgent need to develop new anticancer drugs that can overcome resistance in TNBC via non-apoptotic cell death mechanisms.  

Invention Description 

Researchers from the University of Toledo have developed a method to selectively induce necroptosis and inhibit autophagy using thieno-pyrimidin-4-yl-hydrazinylidene compounds for the treatment of TNBC. 

Applications

• The compounds may be used as chemotherapy to target TNBC
• The compounds may be used as chemo-adjuvants in combination with conventional therapeutics that suffer from drug resistance, toxicity, poor pharmacokinetic profile and efficacy
• The compounds may also be used as pharmacological probes

Advantages

• The compounds may be used as chemotherapy to target TNBC
• The compounds may be used as chemo-adjuvants in combination with conventional therapeutics that suffer from drug resistance, toxicity, poor pharmacokinetic profile and efficacy
• The compounds may also be used as pharmacological probes

Patent Pending US 2021/0154197 A1

Publications 

Tiwari et al. Novel thienopyrimidine analog TPH104 induces immunogenic cell death in TNBC cells. AACR Annual Meeting 2020. DOI: 10.1158/1538-7445.AM2020-2406

Tiwari et al. Necroptosis inducing thienopyridine analogs overcomes chemoresistance in TNBC. AACR Annual Meeting 2020. 10.1158/1538-7445.AM2020-4119