Treosulfan (l-threitol-1,4-bis-methanesulfonate; dihydroxybusulfan) is a prodrug of a bifunctional alkylating cytotoxic agent that is approved for the treatment of ovarian carcinomas in a number of European countries. The antitumor activity of treosulfan has been shown in a variety of solid tumors. It is used for the treatment of all types of ovarian cancer, either supplementary to surgery or palliatively. Treosulfan is a prodrug that is converted nonenzymatically first to a mono-epoxide – (2S,3S)- 1,2-epoxy-3,4-butanediol-4-methanesulfonate – and then to a diepoxide – l-diepoxybutane, which is also a metabolite of butadiene – under physiological conditions. Such conversions are assumed to account for the alkylating and therapeutic activities of treosulfan.

X-396 (Ensartinib) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile. Ensartinib is currently in a global phase 3 trial in ALK positive non-small cell lung cancer (NSCLC) patients. The phase 1/2 clinical findings support the preclinical results that the use of ensartinib may result in favorable therapeutic outcomes in patients with ALK NSCLC, including patients with CNS metastases. In this study, ensartinib was generally well tolerated with the most common adverse event being a rash.

Nirmatrelvir (PF-07321332) is a new oral antiviral drug developed by Pfizer. Nirmatrelvir is a major bioavailable oral SARS-CoV-2 protease inhibitor with in vitro human coronavirus antiviral activity, and excellent selection of off-target and in vivo immune profiles. The combination of ritonavir and nirmatrelvir under the brand name Paxlovid was approved by the FDA on May 25, 2023, for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also referred to as 3C-like protease (3CLpro) or nonstructural protein 5 (nsp5) protease. Inhibition of SARS-CoV-2 Mpro renders it incapable of processing the viral polyproteins pp1a and pp1ab, preventing viral replication. Nirmatrelvir inhibited the activity of recombinant SARS-CoV-2 Mpro in a biochemical assay with a Ki value of 3.1 nM and an IC50 value of 19.2 nM. Nirmatrelvir was found to bind directly to the SARS-CoV-2 Mpro active site by X-ray crystallography.

Zavegepant is a third generation, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist being developed by Pfizer, under a license from Bristol-Myers Squibb, for the prevention and treatment of chronic and episodic migraine. In March 2023, zavegepant nasal spray (ZAVZPRET™) received its first approval in the USA for the acute treatment of migraine with or without aura in adults, based on two randomized, double-blind, placebo-controlled studies. Clinical development of an oral formulation of zavegepant is currently underway.

Pirtobrutinib is a small molecule, noncovalent inhibitor of BTK. BTK is a signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models. On January 27, 2023, the Food and Drug Administration (FDA) granted accelerated approval to pirtobrutinib (Jaypirca, Eli Lilly and Company) for relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

Durlobactam is a new member of the diazabicyclooctane class of beta-lactamase inhibitors with broad-spectrum activity against Ambler class A, C, and D serine beta-lactamases. Sulbactam is a first-generation beta-lactamase inhibitor with activity limited to a subset of class A enzymes that also has direct-acting antibacterial activity against Acinetobacter spp. The latter feature is due to sulbactam's ability to inhibit certain penicillin-binding proteins, essential enzymes involved in bacterial cell wall synthesis in this pathogen. Because sulbactam is also susceptible to cleavage by numerous beta-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. In May 2023, the FDA approved Innoviva’s antibiotic, sulbactam-durlobactam (Xacduro), for treatment in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of ABC.

Fruquintinib is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose, with lower off-target toxicities compared to other targeted therapies. Mechanistically, Fruquintinib selectively blocks VEGF-mediated receptor autophosphorylation, thus inhibiting endothelial cell proliferation and migration. In preclinical in vitro studies using a 32P-ATP assay, Fruquintinib selectively inhibited the tyrosine kinase activity associated with VEGFR-1, VEGFR-2, and VEGFR-3 at concentrations in the nanomolar range, but showed little inhibition against a panel of 254 kinases related to cell cycle or cell proliferation, including cyclin-dependent kinase (CDK1, 2, 5), the epidermal growth factor receptor (EGFR), the mesenchymal-epithelial transition factor (c-Met), and platelet-derived growth factor receptor β (PDGFRβ) kinase. In cellular assays, Fruquintinib potently inhibited VEGF-stimulated VEGFR phosphorylation and proliferation in human umbilical vein endothelial cells. Fruquintinib demonstrated potent antiangiogenic effect and anti-tumor activity in xenograft models of colon adenocarcinoma (HT-29), non-small cell lung cancer (NSCLC; NCI-H460), renal clear cell carcinoma (Caki-1), and gastric carcinoma (BGC823) in mice treated for 3 weeks. Fruquintinib is currently under joint development in China by Chi-Med and its partner Eli Lilly and Company (“Lilly”). Chi-Med and Lilly jointly announced top-line results from the FRESCO CRC trial on March 3, 2017. In addition, Fruquintinib is being studied in China in Phase III pivotal trial in non-small cell lung cancer (“NSCLC”), known as FALUCA; and a Phase II study using Fruquintinib combined with Iressa® (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC.

Nirogacestat (PF-3084014) is a tetralin imidazole gamma-secretase inhibitor. Gamma-secretase, a proteolytic enzyme complex, mediates processing of several integral membrane proteins including amyloid precursor protein and Notch. This compound can inhibit both Notch-related pathway in neoplasia and reduces amyloid-β production. Nirogacestat (PF-3084014) is under development by Pfizer for the treatment of cancer.

Leniolisib (JOENJA®) is an oral selective phosphoinositide 3-kinase-delta (PI3Kdelta) inhibitor being developed by Pharming Group NV in-licensed from Novartis for the treatment of immunodeficiency disorders. Leniolisib inhibits PI3K-delta by blocking the active binding site of PI3K-delta. In cell-free isolated enzyme assays, leniolisib was selective for PI3K-delta over PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome. In cell-based assays, leniolisib reduced pAKT pathway activity and inhibited proliferation and activation of B and T cell subsets. Gain-of-function variants in the gene encoding the p110-delta catalytic subunit or loss of function variants in the gene encoding the p85-alpha regulatory subunit each cause hyperactivity of PI3K-delta. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and to the dysregulation of B and T cells. In March 2023, leniolisib received its first approval for the treatment of activated PI3Kdelta syndrome (APDS) in adult and paediatric patients 12 years of age and older. Leniolisib is also under regulatory review in European Union for the treatment of APDS. Development of leniolisib for the treatment of Sjögren's syndrome has been discontinued.

Fezolinetant (VEOZAH™) is an oral, small molecule, neurokinin 3 receptor (NK3R) antagonist, which is being developed by Astellas Pharma Inc. for the treatment of moderate to severe vasomotor symptoms (VMS) or hot flashes due to menopause. Inhibiting NK3R-mediated signaling in the central nervous system is a non-hormonal strategy to modulate the activity of neurons that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. VEOZAH is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. Fezolinetant has a high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity to NK1 or NK2 receptors. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause.