In Multiple Myeloma (MM), aberrant DNA repair pathways contribute to the development of drug resistance, disease progression, and malignant transformation; as a result, these pathways may be therapeutically exploited. The rate-limiting enzyme for the production of deoxyribonucleotides (dNTPs), which are necessary for DNA replication and DNA damage repair, is ribonucleotide reductase (RNR). In this study, we investigated the activity of 4-hydroxysalicylanilide (HDS), a new RNR inhibitor, in myeloma cells in a xenograft model. Additionally, we evaluated HDS's clinical efficacy and security in MM patients.

PTC596 is a tubulin-binding small molecule under research. PTC596 is orally accessible and is not a P-glycoprotein substrate, in contrast to other tubulin-binding compounds. The interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical in vitro anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in various preclinical mouse models of leiomyosarcomas and glioblastoma in order to characterise PTC596 and position the molecule for optimal clinical development. PTC596's specific essential interactions with tubulin's colchicine site were discovered using X-ray crystallography. Broad-spectrum anticancer action was shown by PTC596. In mice models of leiomyosarcomas and glioblastoma, PTC596 demonstrated efficacy as monotherapy as well as additive or synergistic efficacy in combinations. In a glioblastoma orthotopic model when temozolomide was inactive, PTC596 showed effectiveness.

PTC596 monotherapy medication exposures in a first-in-human phase I clinical study in cancer patients were compared to those that were anticipated to be effective based on mice models. In a clinical trial for adults with leiomyosarcoma, PTC596 is being examined in conjunction with dacarbazine, while in a clinical trial for kids with diffuse intrinsic pontine glioma, it is being tested in combination with radiation.

A promising target for the therapy of solid tumours has emerged: KRASG12C. This long-time "undruggable" target has been demonstrated to be disrupted by covalent inhibitors that target the mutant cysteine-12 residue, however therapeutically effective inhibitors have not yet been discovered. Here, we describe our efforts to find inhibitors suited for clinical development by utilising a cryptic pocket (H95/Y96/Q99) in KRASG12C that we discovered.

We report structure-based design initiatives that resulted in the discovery of a novel quinazolinone scaffold as well as optimization initiatives that resolved a configurational stability problem brought on by constrained rotation around an axially chiral biaryl bond. Following biopharmaceutical optimization of the leading leads, AMG 510, a highly effective, selective, and well-tolerated KRASG12C inhibitor currently undergoing phase I clinical trials, was discovered.

Cancer Clinical Research peer reviewed, open access periodical dedicated to publish the clinical advancements in the cancer research and therapy providing end-to-end solutions, from diagnosis thorough various stages of cancer therapy, pharmaceutical advancements, drug delivery, clinical trials, rehabilitation and care.

Authors can submit their manuscripts as an email attachment to ccr@alliedacademiesscholars.com.

Best Wishes,

Journal Co-ordinator

Journal of Cancer Clinical Research