A5008105524- Cancer Mechanisms and Therapy
- Phytochemical compounds biological activities
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Synthesis and biological activity
- Abdominal Trauma and Injuries
- Reproductive Biology and Fertility
- Prostate Cancer Treatment and Research
- Sperm and Testicular Function
- Pneumonia and Respiratory Infections
- Ovarian function and disorders
- Immunodeficiency and Autoimmune Disorders
- Renal Diseases and Glomerulopathies
- Synthesis and Biological Evaluation
- Quinazolinone synthesis and applications
- Liver Disease Diagnosis and Treatment
- Microscopic Colitis
Bristol-Myers Squibb (United States)
2024
Amgen (United States)
2014-2019
Specialty Materials (United States)
2004-2005
The high expression of proviral insertion site Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role promoting cell survival proliferation while suppressing apoptosis. three isoforms Pim protein appear largely redundant their oncogenic functions. Thus, pan-Pim kinase inhibitor highly desirable. However, active inhibitors have proven difficult develop because Pim-2 has low Km for ATP therefore requires...
The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim inhibitors will have utility the treatment lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized potential for macrocyclization developed series 13-membered macrocycles. structure-activity relationships macrocyclic linker were systematically explored, leading to 9c as potent, subnanomolar inhibitor Pim-1 -2. This...
Abstract The androgen receptor (AR) is a key driver of the cellular processes that contribute to pathology prostate cancers at most stages, and drugs inhibit activity this or interfere with biosynthesis have become cornerstone treatments for cancer. While both types therapy had significant positive impact on disease progression overall survival, de novo acquired resistance remains an impediment durable clinical response in patients metastatic castration-resistant cancer (mCRPC). mechanisms...
Pim kinases are a family of constitutively active serine/threonine that partially redundant and regulate multiple pathways important for cell growth survival. In human disease, high expression the three isoforms has been implicated in progression hematopoietic solid tumor cancers, which suggests kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe structure-guided optimization series quinazolinone-pyrrolodihydropyrrolone analogs leading to identification...
Abstract Pim-1,-2, and -3 are constitutively active serine-threonine kinases which partially redundant regulate multiple pathways important for tumor growth survival. One or more of the human Pims over-expressed in hematological types (e.g. myeloma (MM), NHL AML) some solid tumors prostate SCLC). Pim over-expression correlates with malignancy poor prognosis several indications. Our goal was to generate a pan kinase inhibitor acceptable physical chemical properties vivo anti-tumor efficacy....
Abstract The three members of the Pim kinase family, Pim-1, -2, and -3, are established oncogenes attractive targets in hematological malignancies. We have developed multiple potent selective scaffolds pan-Pim inhibitors with picomolar enzymatic potency nanomolar cellular potency. Using these agents, we observed that abolishment activity impairs tumor cell viability settings, both vitro vivo. numerous assays to measure protein levels activity, including downstream markers p-PDCD4 p-BAD,...