标题: Targeted Cancer Treatment (III) [打印本页] 作者: choi 时间: 昨天 11:31 标题: Targeted Cancer Treatment (III) Additions (all capitalized) to the two postings Tarfeted Cancer Treatment (I) and (II) are as followed.
Tarfeted Cancer Treatment (I) (1)(b)(i)(B) At the time associate professor at Department of Hematology, University of Chicago, Janet D Rowley DEPLOYED GIEMSA STAIN https://en.wikipedia.org/wiki/Giemsa_stain
-- DEVELOPED IN 1904; RENDERING BANDING PATTERN OF CHROMOSOMES -- TO PINPOINT CHROMOSOMAL TRANSLOCATION. SHE DID NOT KNOW WHAT GENES WERE INVOLVED AT THE TRANSLOCATION (AS 1973 WAS AT THE DAWN OF DNA SEQUENCING: AMERICAN WALTER GILBERT REPORTED CHEMICAL METHOD (IF DNA SEQUENCING) THAT YEAR, TO BE FOLLOWED IN 1975 BY ENGLISHMAN FREDERICK SANGER'S ENZYMATIC METHOD.
Fox Chase is now a neighborhood in City of Philadelphia, FROM WHICH THE CANCER CENTER GOT THE NAME.
Tarfeted Cancer Treatment (II) (2)(b)(ii) Arter C et al (of University of Leeds, England), Structural Features of the Protein Kinase Domain and Targeted Binding by Small-Molecule Inhibitors. Journal of Biological Chemistry, 298: 102247 (2022; review). https://pubmed.ncbi.nlm.nih.gov/35830914/
Quote:
Abstract: "Most kinase inhibitors are ATP competitive, deriving potency by occupying the deep hydrophobic pocket [ATP-binding site] at the heart of the kinase domain."
Go to Figure 1, whose caption at the last sentence reminded a reader that this figure is Aurora-A, a serine-threonine (protein) kinase -- not c-abl/ ABL1 tyrosine kinase. But these two kinds of kinase are closely related enough to merit discussion together.
Fig 1A has 2 panels, the right panel is obtained by rotating the left panel 90 degrees to the left. Heed the substrating binding [SHOULD BE 'SUBSTRATE-BINDING'] site of eggplant shape circumscribed by dotted line.
Fig 1B is the magnified view of Fig 1A left panel (focusing on the ATP-binding site in the N-lobe of kinase domain), with ATP now presented in BOTH space-filling [SHOULD BE 'SPACE-FILLING'] and stick models, with the three (negatively charged) phosphates of ATP pointing to the right and stabilized by a (positively charged) magnesium ion right below.
(2)(b)(iii) Reference 129 was Awad MM et al. Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1. New England Journal of Medicine, 368: 2395 (2013) https://www.nejm.org/doi/full/10.1056/NEJMoa1215530
("The glycine at position 2032 is conserved in all human ROS1 paralogs and in several other, more distantly related tyrosine and serine–threonine kinases * * * ROS1 BINDS CRIZOTINIB AT THE ATP-BINDING SITE IN THE CLEFT BETWEEN THE N-TERMINAL AND C-TERMINAL DOMAINS OF THE KINASE.20 * * * AN ARGININE AT POSITION 2032 [MUTATED FROM WILD-TYPE GLYCINE AT THIS POSITION] HAS BEEN MODELED INTO AN EMPTY ROS1 ATP–INHIBITOR BINDING SITE (FIGURE 3D) AND IS BELIEVED TO STERICALLY CLASH WITH THE PIPERIDINE RING OF CRIZOTINIB WHILE STILL ALLOWING FOR ATP BINDING") (emphasis added)
THE FOLLOWIN TWO PARAGRAPHS (c) AND (d) ARE TOTALLY NEW. (2)(c) The latest drug for this patient is zidesamtinib, which is experimental and not approved by FDA yet.
(i) Pipeline. Nuvalent Inc, undated https://nuvalent.com/pipeline/
(zidesamtinib in phase 2 of clinical trial)
Nuvalent Inc is a pharmaceutical company based in Cambridge, Mass since 2017.
(ii) Press release: Nuvalent Announces Positive Pivotal Data from ARROS-1 Clinical Trial of Zidesamtinib for TKI Pre-treated Patients with Advanced ROS1-positive NSCLC. Nuvalent Inc, https://investors.nuvalent.com/2 ... ROS1-positive-NSCLC
("Zidesamtinib demonstrated intracranial responses [in other words, penetrating blood-brain barrier], activity against tumors with a ROS1 G2032R resistance mutation [at ATP-binding site], and a generally well-tolerated safety profile")
There is no need to read the rest of the press release, but if you do, here is the table for acronyms:
NDA = new drug application
BICR = Blinded Independent Central Review of the Progression-Free Survival Endpoint
ORR = objective response rate (which FDA defines as "the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period") (2)(d) Patients with Philadelphia chromosome-positive chronic myeloid leukemia are invariably old. Following treatment with imatinib, they die of old age or other diseases -- many years later. I did not give a thought whether they are cured.
However, lung cancer patients with gene arrangements tend to be very young. Reading this WSJ article got me thinking: All these tyrosine kinase inhibitors (TKIs), starting imatinib, do not even attempt to kill cancer cells; rather they (TKIs) shut down mutated (tyrosine kinase) genes. Patients live with the cancer cells, which will mutate successfully a couple of years later to render the treatment obsolete and require a new regiment. On the other hand, to kill cancer cells entails a lot of side effects.
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This posting (attached below) is the last of the series.
